Metal cataltsts and methods for making and using same

ABSTRACT

Compounds having the formula:                    
     are disclosed. M 1  and M 2  are the same or different and are transition metal atoms or ions; Z 2  and Z 3 , independently, are the atoms necessary to complete a 3-12 membered heterocyclic ring; Z 1  is an alkylene or arylene group; Q 1  and Q 2  are the same or different and are electron withdrawing groups; L 1  and L 3 , taken together, represent —O—CR 13 —O—; L 2  and L 4 , taken together, represent —O—CR 14 —O—; and R 13  and R 14  are the same or different and are selected from the group consisting of alkyl groups and aryl groups or R 13  and R 14  represent alkylene or arylene groups that are directly or indirectly bonded to one another. Methods for making such compounds are also disclosed, as are intermediates which can be used in their preparation. Also disclosed are methods for carrying out C—H insertion reactions using bis-transition metal catalysts, such as the above compounds. Procedures for preparing d-threo methylphenidate, tolterodine, CDP-840, nominfensine, and sertraline, are described.

The present application claims the benefit of U.S. Provisional PatentApplication Serial No. 60/131,262, filed Apr. 27, 1999.

The present invention was made with the support of the National ScienceFoundation Contract No. CHE 9726124 and National Institutes of HealthContract Nos. DA06301 and DA05886. The Federal Government may havecertain rights in this invention.

FIELD OF THE INVENTION

The present invention relates to metal catalysts and, more particularly,to bis transition metal catalysts and to methods for making and usingsame.

BACKGROUND OF THE INVENTION

Catalysts

In recent years, it has become widely recognized that ligands having C₂symmetry can be used with great effect in the design of catalysts forasymmetric synthesis. Several reviews have addressed the use of suchcatalysts in asymmetric carbenoid reactions. These include: Singh etal., “Catalytic Enantioselective Cyclopropanation of Olefins UsingCarbenoid Chemistry,” Synthesis, 1997:137-149 and Doyle, Chiralcatalysts for Enantioselective Carbenoid Cyclopropanation Reactions,”Recl. Trav. Chim. Pays-Bas, 110:305-316 (1991). The use of thesecatalysts in asymmetric transformations has also been reported inPfaltz, “Chiral Semicorrins and Related Nitrogen Heterocycles as Ligandsin Asymmetric Catalysts,” Acc. Chem. Res., 26:339-345 (1993); Noyori,Asymmetric Catalysis in Organic Synthesis, New York: John Wiley & Sons,Inc., pp. 16-95 (1994); Evans et al., “Bis(oxazoline)-copper Complexesas Chiral Catalysts for the Asymmetric Aziridination of Olefins,” J. Am.Chem. Soc., 115:3328-3329 (1993); Li et al., “Asymmetric AlkeneAziridination With Readily Available Chiral Diimine-based Catalysts,” J.Am. Chem. Soc., 115:5326-5327 (1993); Nishikori et al., “Catalytic andHighly Enantioselective Aziridination of Styrene Derivatives,”Tetrahedron Lett., 37:9245-9248 (1996); Nicholas et al., “On theMechanism of Alyllic Amination Catalyzed by Iron Salts,” J. Am. Chem.Soc., 119:3302-3310 (1997); Johnson et al., “Catalytic AsymmetricEpoxidation of Allylic Alcohols,” in Ojima, ed., Catalytic AsymmetricSynthesis, New York: VCH Publishers, Inc., pp. 103-158 (1993); andJacobsen, “Asymmetric Catalytic Epoxidation of UnfunctionalizedOlefins,” in Ojima, ed., Catalytic Asymmetric Synthesis, New York: VCHPublishers, Inc., pp. 159-202 (1993). The C₂ symmetry of a complex cutsin half the number of possible arrangements that are available for thereacting substrate or substrates. Consequently, it becomes much easierto design a catalyst with well-defined chiral influence to effect highasymmetric induction of the reaction in question. A natural extensionfor chiral catalyst design would be to move from complexes having C₂symmetry to complexes having D₂ symmetry. Catalysts having D₂ symmetrywould cut to a quarter the number of possible arrangements that reavailable for the reacting substrate or substrates and, thus, would havethe potential of being very reliable chiral catalysts.

Even though the concept of using catalysts having D₂ symmetry is a veryattractive proposition, the practical outcome of trying to delvelop suchcatalysts has not had much success. The general strategy, such as thatdescribed in Maxwell et al., “Shape-selective and AsymmetricCyclopropanation of Alkenes Catalyzed by Rhodium Porphyrins,”Organometallics, 11:645-652 (1992) (“Maxwell”), Morice et al.,“Oxidation and Chiral Recognition of Amino Esters by Dioxoruthenium(VI)Porphyrins: Synthesis of a New Imino Ester Ru(II) Complexes,”Tetrahedron Lett., 37:6701-6704 (1996), and Halterman et al., “Synthesisof D₂-symmetric Benzaldehydes and Achiral Arylsipyrromethanes,”Tetrahedron Lett., 37:6291-6294 (1996), has been to develop veryelaborate D₂ ligands built around a porphyrin core. However, thesynthetic procedures for these ligands are long and give poor yields,and the resulting chiral catalysts perform only with moderate asymmetricinduction. Maxwell suggests that one problem with these porphyrincomplexes is that the chiral influence is too far removed from the metalcenter to be very effective in asymmetric induction.

In view of the unrealized promise of catalysts having D₂ symmetry, thereis a need for catalysts having D₂ symmetry which are easily to produceand which have high asymmetric inductive effects. The present invention,in part, is directed to meeting this need.

Synthesis of Gem-Diarylalkyl Derivatives

The gem-diarylalkyl group is present in a number of importantpharmaceuticals, such as tolterodine, CDP-840, and nomifensine, andsertraline. Consequently, a number of reports have recently appeareddescribing methods for the asymmetric synthesis of gem-diarylalkylderivatives. These include: Frey et al., J. Org. Chem., 63:3120-3124(1998) (“Frey”); Andersson et al., J. Org. Chem., 63:8067-8070 (1998)(“Andersson”); Houpis et al., Tetrahedron Lett., 38:7131-7134 (1997)(“Houpis”); Christenson et al., Tetrahedron, 47:4739-4752 (1991)(“Christenson”); Alexakis et al., Tetrahedron Lett., 29:4411-4414 (1988)(“Alexakis”); and Corey et al., Tetrahedron Lett., 35:5373-5376 (1994)(“Corey”). Particularly effective have been the asymmetric conjugateaddition of organometallic reagents to cinnamates, decribed in Frey,Andersson, Houpis, Christenson, and Alexakis, and the aryl cuprateaddition to enantiomerically pure dimethyl2-phenylcyclopropane-1,1-dicarboxylate, described in Corey. However,these reaction schemes involve multiple steps with poor overall yieldsand inconsistent chiral purity.

Accordingly, a need continues to exist for methods for preparingasymmetric gem-diarylalkyl derivatives. The present invention, in part,is directed to meeting this need.

Formation of Carbon-Carbon Bonds

The aldol reaction is a central transformation in organic synthesis.See, for example, Heathcock in Morrison, ed., Asymmetric Synthesis, SanDiego: Academic Press, Vol. 3, Chapter 2 (1984) (“Heathcock”). Not onlyis the reaction a powerful carbon-carbon bond forming process, but,also, Heathcock reports that the reaction can be made highlydiastereoselective by using enolates of defined geometry. Furthermore,high enantioselectivity can be achieved by using chiral auxiliaries(Heathcock) or by using chiral catalysts. The use of chiral catalysts inenantioselective aldol reactions has been recently reviewed in Nelson,“Catalyzed Enantioselective Aldol Additions of Latent EnolateEquivalents,” Tetrahedron-Asymmetry, 9:357-389 (1998). Of particularinterest are aldol reactions between enolates of arylacetates andaldehydes. For example, Evans et al., “C-2-symmetric Copper(II)Complexes as Chiral Lewis Acids. Scope and Mechanism of the CatalyticEnantioselective Aldol Additions of Enolsilanes to Pyruvate Salts,” J.Am. Chem. Soc., 121:669-699 (1999), recently reported a reaction betweena silylketene acetal of phenylacetate and benzyloxyacetaldehyde using aCu(II) bisoxazoline complex. The reaction resulted in lowenantioselectivity (about 9%) and no diastereoselectivity. However,better asymmetric induction has been achieved in such aldol reactions byusing chiral enolates (Lutzen et al., “D-xylose DerivedOxazolidin-2-ones as Chiral Auxiliaries in Stereoselective AldolReactions,” Tetrahedron-Asymmetry. 8:1193-1206 (1997)). However,processes of this type occurring in high yields and with gooddiastereoselectivity and enantioselectivity has not been reported.

Accordingly, a need continues to exist for methods for formingcarbon-carbon bonds with good diastereoselectivity andenantioselectivity. The present invention, in part, is directed tomeeting this need.

RITALIN™ and its Congeners

Attention Deficit Disorder (“ADD”) is the most commonly diagnosedillness in children. Symptoms of ADD include distractibility andimpulsivity. A related disorder, termed Attention Deficit HyperactivityDisorder (“ADHD”), is further characterized by increased symptoms ofhyperactivity in patients. Racemic methylphenidate (e.g., RITALIN™) is amild central nervous system stimulant, with pharmacological activityqualitatively similar to amphetamines, and has been the drug of choicefor symptomatic treatment of ADD in children. Current administration ofracemic methylphenidate, however, results in notable side effects, suchas anorexia, weight loss, insomnia, dizziness, and dysphoria.Additionally, racemic methylphenidate, which is a Schedule II controlledsubstance, produces a euphoric effect when administered intravenously orthrough inhalation and, thus, carries a high potential for substanceabuse in patients.

At least 70% individuals who are infected with the HumanImmunodeficiency Virus (“HIV”) who have developed AcquiredImmunodeficiency Syndrome (“AIDS”) eventually manifest cognitivedefects, and many display signs and symptoms of dementia. Complaints offorgetfulness, loss of concentration, fatigue, depression, loss ofattentiveness, mood swings, personality change, and thought disturbanceare common in patients with HIV disease. Racemic methylphenidate hasbeen used to treat cognitive decline in AIDS patients. As describedabove, racemic methylphenidate, which is a Schedule II controlledsubstance, produces a euphoric effect when administered intravenously orthrough inhalation, and thus carries a high potential for drug abuse inAIDS patients.

Glutathione is an important antioxidative agent that protects the bodyagainst electrophilic reactive compounds and intracellular oxidants. Ithas been postulated that HIV-AIDS patients suffer from drughypersensitivity due to drug overload and an acquired glutathionedeficiency. Patients with HIV infection have demonstrated a reducedconcentration of glutathione in plasma, cells, and broncho-alveolarlavage fluid. Clinical data suggest that HIV-seropositive individualsdisplay adverse reactions to the simultaneous administration of severalotherwise therapeutic drugs. It is therefore desirable to provide forthe administration of methylphenidate in reduced dosages among patientswith drug hypersensitivity due to HIV infection.

Methylphenidate possesses two centers of chirality and thus can exist asfour separate stereoisomers. Diastereomers are known in the art topossess differing physical properties, such as melting point and boilingpoint. For example, while the threo-racemate of methylphenidate producesthe desired effect on the cental nervous system, the erythro-racematecontributes to hypertensive side-effects and exhibits lethality in rats.

Additional studies in animals, children and adults have demonstratedpharmacological activity in the d-threo isomer of methylphenidate(2R:2′R). Although the role of the l-threo isomer in toxicity or adverseside effects has not been thoroughly examined, the potential for isomerballast in methylphenidate is of concern for many patients, particularlythose drug hypersensitive patients described above.

Although l-threo-methylphenidate is rapidly and stereo-selectivelymetabolized upon oral administration, intravenous administration orinhalation results in high l-threo-methylphenidate serum levels.Intravenous administration and inhalation are the methods of-choice bydrug abusers of current methylphenidate formulations, and it has beenpostulated that the euphoric effect produced by current formulations ofmethylphenidate is due to the action of the l-threo-methylphenidate.

Accordingly, it has been suggested that the use of the d-threo isomer(2R:2′R) of methylphenidate which is substantially free of the l-threoisomer produces high methylphenidate activity levels and simultaneouslyreduces methylphenidate's euphoric effect and the potential for abuseamong patients.

Methods for synthesizing d-threo methylphenidate have been reported.However, these methods involve long, complicated syntheses, have pooroverall yields, and require at least some separation of mixtures ofenantiomers and/or diastereomers.

In view of the advantages of pure d-threo methylphenidate and thedeficiency in the art of methods for making this compound and itscongeners, a need exists for an improved synthetic method for makingpure d-threo methylphenidate and its congeners. The present invention,in part, is directed to meeting this need.

SUMMARY OF THE INVENTION

The present invention relates to a compound having the formula:

wherein M¹ and M² are the same or different and are transition metalatoms or ions; Z² and Z³, independently, are the atoms necessary tocomplete a 3-12 membered heterocyclic ring; Z¹ is an alkylene or arylenegroup; Q¹ and Q² are the same or different and are electron withdrawinggroups; L¹ and L³, taken together, represent —O—CR¹³—O—; L² and L⁴,taken together, represent —O—CR¹⁴—O—; and R¹³ and R¹⁴ are the same ordifferent and are selected from the group consisting of alkyl groups andaryl groups or R¹³ and R¹⁴ represent alkylene or arylene groups that aredirectly or indirectly bonded to one another.

The present invention also relates to a compound which includes a firstmetal atom and a second metal atom that are bonded to one another alongan axis and two carboxylate ligands. Each of the two carboxylate ligandsincludes two carboxylate groups bonded to each other via a moiety havingthe formula:

where Z¹⁰ and Z¹¹, together with the atoms to which they are bonded forma 3-12 membered ring; Z^(10′) and Z^(11′), together with the atoms towhich they are bonded form a 3-12 membered ring; and R⁷⁸, R^(78′), R⁷⁹,and R^(79′) are independently selected from the group consisting of H,an alkyl group, and an aryl group. Z¹² is an alkylene or arylene group.Each of the two carboxylate groups includes a first carboxylate oxygenatom (“O¹”) , a second carboxylate oxygen atom ( “O²”), and a carbon(“C”) to which the O¹ and the O² are bonded thereby forming two O¹—C—O²moieties, and each O¹—C—O² moiety defines a plane which is substantiallyparallel to the axis. O¹ of each of the two carboxylate groups of eachof the two carboxylate ligands is bonded to the first metal atom, and O²of each of the two carboxylate groups of each of the two carboxylateligands is bonded to the second metal atom. Each of the two carboxylateligands further includes at least two chiral centers, and the compoundhas D₂ symmetry.

The present invention also relates to a method for making a compoundhaving the formula:

wherein M¹ and M² are the same or different and are transition metalatoms or ions; Z² and Z³, independently, are the atoms necessary tocomplete a 3-12 membered heterocyclic ring; Z¹ is an alkylene or arylenegroup; Q¹ and Q² are the same or different and are electron withdrawinggroups; L¹ and L³, taken together, represent —O—CHR¹³—O—; L² and L⁴,taken together, represent —O—CHR¹⁴—O—; and R¹³ and R¹⁴ are the same ordifferent and are selected from the group consisting of alkyl groups andaryl groups or R¹³ and R¹⁴ represent alkylene or arylene groups that aredirectly or indirectly bonded to one another. The method includesproviding a ligand having the formula:

or a mixture thereof, wherein each of A¹ and A² is independentlyselected from the group consisting of a hydrogen atom and an electronwithdrawing group and wherein each of R³ and R⁴ is independentlyselected from the group consisting of H, alkyl, and aryl. The methodfurther includes converting the ligand with a bis-metal salt underconditions effective to produce the compound.

The present invention also relates to compounds having one of thefollowing formulae:

wherein Z² and Z³, independently, are the atoms necessary to complete a3-12 membered heterocyclic ring; Z¹ is an alkylene or arylene group; A¹and A² are independently selected from the group consisting of ahydrogen atom and an electron withdrawing group; and each each of R³ andR⁴ is independently selected from the group consisting of H, alkyl, andaryl.

The present invention also relates to a method for preparing anN-substituted compound having the formula:

wherein Z² and Z³, independently, are the atoms necessary to complete a3-12 membered heterocyclic ring; Z¹ is an alkylene or arylene group; A³and A⁴ are the same or different and are electron withdrawing groupshaving the formulae —C(O)R², —SO₂R², or —P(O)R²R²; each of R¹, R^(1′),R², and R^(2′) is an alkyl group, an aryl group, or an alkoxy group; andeach of R³ and R⁴ is independently selected from the group consisting ofH, alkyl, and aryl. The method includes providing an N-unsubstitutedcompound having the formula:

wherein each of R⁶ and R⁷ is independently selected from an alkyl groupor an aryl group. The method further includes converting theN-unsubstituted compound to the N-substituted compound with an acylatingagent, a sulfonylating agent, or a phosphonylating agent.

The present invention also relates to a method for preparing anN-unsubstituted compound having the formula:

wherein Z² and Z³, independently, are the atoms necessary to complete a3-12 membered heterocyclic ring; Z¹ is an alkylene or arylene group; andR⁶ and R⁷ are independently selected from an alkyl group or an arylgroup. The method includes providing an unsaturated heterocycliccompound having the formula:

and converting the unsaturated heterocyclic compound to theN-unsubstituted compound using hydrogenation.

The present invention, in still another embodiment thereof, relates to acompound having one of the following formulae:

wherein Z² and Z³, independently, are the atoms necessary to complete a3-12 membered heterocyclic ring; Z¹ is an alkylene or arylene group; andR⁶ and R⁷ are independently selected from an alkyl group or an arylgroup.

The present invention also relates to a method for preparing anunsaturated heterocyclic compound having the formula:

wherein Z² represents the atoms necessary to complete a 3-12 memberedheterocyclic ring; Z¹ is an alkylene or arylene group; and R⁶ isselected from an alkyl group or an aryl group. The method includesproviding a cyclic ketone having the formula:

wherein R⁸ is an amine-protecting group. The method further includesconverting the cyclic ketone to the N-unsaturated heterocyclic compoundwith a bis-lithium compound having the forrmula Z¹Li₂.

The present invention further relates to a method of producing acompound having the formula:

where R¹, R², and R³ are independently selected from H, alkyl, aryl, orvinyl or where R¹ and R³, together with the atoms to which they arebonded, form a 5-12 membered ring; Y is an electron withdrawing group; Xis CH₂, O, or NR¹¹; R¹¹ is H, an alkyl group, an aryl group, an acylgroup, an alkoxycarbonyl group, or a silyl group having the formula—SiR³³R³⁴R³⁵; each of R³⁰ and R³¹ is independently selected from thegroup consisting of H, alkyl, aryl, and vinyl; R³² is an alkyl group, anaryl group, an acyl group, an alkoxycarbonyl group, or a silyl grouphaving the formula —SiR³⁶R³⁷R³⁸; or R³¹ and R³², together with the atomsto which they are bonded, form a 5-12 membered ring; R³³, R³⁴, R³⁵, R³⁶,R³⁷, and R³⁸ are independently selected from an alkyl group and an arylgroup; provided that when each of R³⁰ and R³¹ is H, X is not CH₂. Themethod includes providing a diazo compound having the formula:

and converting the diazo compound with a compound having the formula:

in the presence of a bis-transition metal catalyst, under conditionseffective to produce the compound. In the immediately preceding formula,X′ is CH₂, O, or NR^(11′) and R^(11′) is an alkyl group, an aryl group,an acyl group, an alkoxycarbonyl group, or a silyl group. When when X isO or CH₂, when R¹ and R³, together with the atoms to which they arebonded, form a 5-12 membered ring, and when R³¹ and R³², together withthe atoms to which they are bonded, form a 5-12 membered ring,conversion of the diazo compound is carried out substantially in theabsence of oxygen.

In yet another embodiment, the present invention relates to a method forproducing a compound having the formula:

wherein R¹, R², and R³ are independently selected from H, an alkylgroup, an aryl group, or a vinyl group or where R¹ and R³, together withthe atoms to which they are bonded, form a 5-12 membered ring; Y is anelectron withdrawing group; and R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, and R⁵⁹ areindependently selected from the group consisting of H, alkyl, aryl,halogen, and alkoxy. The method includes providing a 1,3-cyclohexadienehaving the formula:

The method further includes converting the 1,3-cyclohexadiene with adiazo compound having the formula:

in the presence of a bis-transition metal catalyst and under conditionseffective to produce the compound.

The present invention also relates to a compound having the formula:

R¹, R², and R³ are independently selected from H, an alkyl group, anaryl group, or a vinyl group, or R¹ and R³, together with the atoms towhich they are bonded, form a 5-12 membered ring. Y is an electronwithdrawing group. R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, and R⁵⁹ are independentlyselected from the group consisting of H, alkyl, aryl, halogen, andalkoxy.

In still another embodiment, the present invention relates to a methodfor making a compound having the formula:

in which R¹, R², and R³ are independently selected from H, an alkylgroup, an aryl group, or a vinyl group or where R¹ and R³, together withthe atoms to which they are bonded, form a 5-12 membered ring; Y is anelectron withdrawing group; and R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁸, and R⁵⁹ areindependently selected from the group consisting of H, alkyl, aryl,halogen, and alkoxy. The method includes providing a cyclohexadienederivative having the formula:

wherein R⁵⁷ is H. The method further includes converting thecyclohexadiene derivative with hydrogenating and oxidizing agents underconditions effective to form the compound.

The present invention also relates to a method for preparing a compoundhaving the formula:

R¹, R², and R³ are independently selected from H, an alkyl group, anaryl group, or a vinyl group, or R¹ and R³, together with the atoms towhich they are bonded, form a 5-12 membered ring; R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁸,and R⁶⁵ are independently selected from the group consisting of H, alkylgroups, aryl groups, halogen, amino groups, alkoxy groups, hydroxygroups, and acid groups; R⁶² represents an alkyl moiety; or R⁶⁵ and R⁶²together represent the atoms necessary to complete a 5-12 membered ring.The method includes providing a cyclohexadiene derivative having theformula:

where R⁵⁷ is H, R⁵⁹ is independently selected from the group consistingof H, alkyl groups, aryl groups, halogens, amino groups, alkoxy groups,hydroxy groups, and acid groups, and Y is an electron withdrawing group.The cyclohexadiene derivative is then converted with hydrogenating andoxidizing agents under conditions effective to form a phenyl derivativehaving the formula:

and the phenyl derivative is converted under conditions effective toproduce the compound.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “alkyl” is meant to include linear alkyls, branchedalkyls, and cycloalkyls, each of which can be substituted orunsubstituted. “Alkyl” is also meant to include lower linear alkyls(e.g., C1-C6 linear alkyls), such as methyl, ethyl, n-propyl, n-butyl,n-pentyl, and n-hexyl; lower branched alkyls (e.g., C3-C8 branchedalkyls), such as isopropyl, t-butyl, 1-methylpropyl, 2-methylpropyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 2-methyl-2-ethylpropyl,2-methyl-1-ethylpropyl, and the like; and lower cycloalkyls (e.g., C3-C8cycloalkyls), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and the like. “Alkyl”, as use herein, is meant to include unsubstitutedalkyls, such as those set forth above, in which no atoms other thancarbon and hydrogen are present. “Alkyl”, as use herein, is also meantto include substituted alkyls. Suitable substituents include aryl groups(which may themselves be substituted), heterocyclic rings (saturated orunsaturated and optionally substituted), hydroxy groups, alkoxy groups(which is meant to include aryloxy groups (e.g., phenoxy groups)), thiolgroups, alkylthio groups, arylthio groups, amine groups (unsubstituted,monosubstituted, or disubstituted, e.g., with aryl or alkyl groups),carboxylic acid groups, carboxylic acid derivatives (e.g., carboxylicacid esters, amides, etc.), phosphine groups, sulfonic acid groups,halogen atoms (e.g., Cl, Br, and I), and the like. Further, alkyl groupsbearing one or more alkenyl or alkynyl substituents (e.g., a methylgroup itself substituted with a prop-1-en-1-yl group to produce abut-2-en-1-yl substituent) is meant to be included in the meaning of“alkyl ”.

As used herein, “alkylene” refers to a bivalent alkyl group, where alkylhas the meaning given above. Linear, branched, and cyclic alkylenes, aswell as examples thereof, are defined in similar fashion with referenceto their corresponding alkyl group. Examples of alkylenes includeeth-1,1-diyl (i.e., —CH(CH₃)—), eth-1,2-diyl (i.e., —CH₂CH₂—),prop-1,1-diyl (i.e., —CH(CH₂CH₃)—), prop-1,2-diyl (i.e., —CH₂—CH(CH₃)—),prop-1,3-diyl (i.e., —CH₂CH₂CH₂—), prop-2,2-diyl (e.g. —C(CH₃)₂—),cycloprop-1,1-diyl, cycloprop-1,2-diyl, cyclopent-1,1-diyl,cyclopent-1,2-diyl, cyclopent-1,3-diyl, cyclohex-1,1-diyl,cyclohex-1,2-diyl, cyclohex-1,3-diyl , cyclohex-1,4-diyl,but-2-en-1,1-diyl, cyclohex-1,3-diyl, but-2-en-1,4-diyl,but-2-en-1,2-diyl, but-2-en-1,3-diyl, but-2-en-2,3-diyl. Also includedin the meaning of the term “alkylene” are compounds having the formula—R′—R″—, where —R′ represents a linear or branched alkyl group and R″—represents a cycloalkyl group, such as moieties having the formula:

As used herein, “aryl” is meant to include aromatic rings, preferablyhaving from 4 to 12 members, such as phenyl rings. These aromatic ringscan optionally contain one or more heteroatoms (e.g., one or more of N,O, and S), and, thus, “aryl”, as used herein, is meant to includeheteroaryl moities, such as pyridyl rings and furanyl rings. Thearomatic rings can be optionally substituted. “Aryl” is also meant toinclude aromatic rings to which are fused one or more other aryl ringsor non-aryl rings. For example, naphthyl groups, benzimidazole groups,and 5,6,7,8-tetrahydro-2-naphthyl groups (each of which can beoptionally substituted) are aryl groups for the purposes of the presentapplication. As indicated above, the aryl rings can be optionallysubstituted. Suitable substituents include alkyl groups (which canoptionally be substituted), other aryl groups (which may themselves besubstituted), heterocyclic rings (saturated or unsaturated), hydroxygroups, alkoxy groups (which is meant to include aryloxy groups (e.g.,phenoxy groups)), thiol groups, alkylthio groups, arylthio groups, aminegroups (unsubstituted, monosubstituted, or disubstituted, e.g., witharyl or alkyl groups), carboxylic acid groups, carboxylic acidderivatives (e.g., carboxylic acid esters, amides, etc.), phosphinegroups, sulfonic acid groups, halogen atoms (e.g., Cl, Br, and I), andthe like.

As used herein, “arylene” is meant to include a bivalent aryl group inwhich both valencies are present on aromatic carbons. Examples of suchgroups include, for example, 1,3-phenylene, 1,4-phenylene,5-methyl-1,3-phenylene, pyrid-2,3-diyl, pyrid-2,4-diyl, pyrid-2,5-diyl,pyrid-3,5-diyl, 1,3-naphthylene, 1,7-naphthylene, 1,8-naphthylene,5,6,7,8-tetrahydro-1,3-naphthylene. “Arylene”, as used herein, is alsomeant to include a bivalent group having the formula —R—R′—, where R isan alkyl group and R′ is an aryl group. As the structure of —R—R′—indicates, one of the valencies is on the R (i.e., alkyl) portion of the—R—R′— moiety and the other of the valencies resides on the R′ (i.e.,aryl) portion of the —R—R′— moiety. Examples of this type of arylenemoiety include moieties having the formulae:

and the like.

As used herein, “alkoxy” is meant to include groups having the formula—O—R, where R is an alkyl or aryl group. They include methoxy, ethoxy,propoxy, phenoxy, 4-methylphenoxy, and the like.

As used herein, “electron withdrawing group” refers to those groupswhich are able to withdraw electron density from adjacent positions in amolecule, as determined, for example, by reference to the tables in theclassical works which establish the classification of varioussubstituents according to their electron withdrawing character. Forexample, reference may be made to the classification established by theHammett scale, such as the one set forth in Gordon et al., The Chemist'sCompanion, New York: John Wiley & Sons, pp. 145-147 (1972), which ishereby incorporated by reference. Suitable electron-withdrawing groupsinclude those having a para a value higher than or equal to about 0.2 orhigher than or equal to about 0.3, with reference to the Hammett scale.Particular examples of electron withdrawing groups are moieties havingthe formulae —C(O)R, —SO₂R, and —P(O)RR′, where R and R′ areindependently selected from an alkyl group, an aryl group, and an alkoxygroup.

As used herein, “ring” refers to a homocyclic or heterocyclic ring whichcan be saturated or unsaturated. The ring can be unsubstituted, or itcan be substituted with one or more substituents. The substituents canbe saturated or unsaturated, aromatic or nonaromatic, and examples ofsuitable substituents include those recited above in the discussionrelating to susbtituents on alkyl and aryl groups. Furthermore, two ormore ring substituents can combine to form another ring, so that “ring”,as used herein, is meant to include fused ring systems. In the casewhere the ring is saturated (i.e., in the case where each of the atomsmaking up the ring are joined by single bonds to other members of thering), the ring may optionally include unsaturated (aromatic ornonaromatic) or saturated substituents.

The present invention relates to a compound which includes a first metalatom and second metal atom that are bonded to one another along an axis.This can be represented by the formula M¹—M², where M¹ and M² representthe first and second metal atoms, repectively, and the dash representsthe bond and the bond axis. The compound also includes two carboxylateligands. As used herein, “carboxylate ligands” means ligands whichcontain one or more carboxylate groups. As used herein, carboxylategroups mean groups having the formula:

which can be written with the following formula:

where the dashed line represents the delocalized electron.Alternatively, the carboxylate group can be expressed without showingthe delocalized electron, as in the following formula:

In the present invention, each of the two carboxylate ligands includestwo carboxylate groups, and these two carboxylate groups are bonded toeach other via a moiety having the formula (“Formula I”):

In Formula I, Z¹⁰ and Z¹¹, together with the atoms to which they arebonded form a 3-12 membered ring, and Z^(10′) and Z^(11′), together withthe atoms to which they are bonded form a 3-12 membered ring.Preferably, Z¹⁰ and Z^(10′) are the same, and each contains aheteroatom, such as a nitrogen, oxygen, or sulfur. More preferably, Z¹⁰and Z^(10′) are the same, and each represents a single heteroatomselected from the group consisting a sulfur atom, an oxygen atom, and anoptionally substituted nitrogen atom. Preferably, at least one of Z¹⁰and Z^(10′) has the formula —NQ—, at least one of Z¹¹ and Z^(11′) is anarylene or alkylene group, and Q is an electron withdrawing group. Stillmore preferably, both of Z¹⁰ and Z^(10′) has the formula —NQ—, both ofZ¹¹ and Z^(11′) is an alkylene group, and Q is an electron withdrawinggroup. Although one of Z¹⁰ and Z¹¹ and/or one of Z^(10′) and Z^(11′) canrepresent a direct bond between the carbons to which they are attached,it is preferred that this not be the case and that none of Z¹⁰, Z¹¹,Z^(10′), and Z^(11′) represents such a direct bond. R⁷⁸, R^(78′), R⁷⁹,and R^(79′) are independently selected from the group consisting of H,an alkyl group, and an aryl group. Preferably, each of R⁷⁸, R^(78′),R⁷⁹, and R^(79′) represents a hydrogen. Z¹² represents an alkylene orarylene group, preferably a substituted or unsubstituted 1,3-phenylenegroup.

As indicated in the formulae above, each of the two carboxylate groupsincludes a first carboxylate oxygen atom (“O¹”) , a second carboxylateoxygen atom (“O²”), and a carbon (“C”) to which the O¹ and the O² arebonded thereby forming two O¹—C—O² moieties. In the compounds of thepresent invention, each O¹—C—O² moiety lies in and defines a plane whichis substantially parallel to the M¹—M² bond axis. O¹ of each of the twocarboxylate groups of each of the two carboxylate ligands is bonded tothe first metal atom M¹; O² of each of the two carboxylate groups ofeach of the two carboxylate ligands is bonded to the second metal atomM². As used in this context, planes which are “substantially parallel”to the M¹—M² bond axis include those planes which do not intersect theM¹—M² bond axis or which intersect the M¹—M² bond axis at an angle ofless than 20°, preferably less than 10°.

Each of the two carboxylate ligands further comprises at least twochiral centers. These centers, for example, can be included in one ormore of Z¹⁰, Z¹¹, Z^(10′), and Z^(11′), and/or they can be located atthe carbon atoms to which Z¹⁰, Z¹¹, Z^(10′), and Z^(11′) are bonded. Thestereochemistry at these chiral moieties are selected such that thecompound, taken as a whole, has D₂ symmetry. Molecules having D₂symmetry are molecules which have a vertical C₂ axis and a set of two C₂axes perpendicular to the vertical C₂ axis. D₂ symmetry is furtherdescribed in, for example, Cotton et al., Advanced Inorganic Chemistry,4th ed., New York: John Wiley & Sons, pages 28-46 (1980), which ishereby incorporated by reference.

Illustrative examples of such compounds and methods of making and usingthem are described below.

The present invention, in another embodiment thereof, relates tocompounds having the formula (“Formula II”):

M¹ and M² are the same or different and are transition metal atoms orions, examples of which include Sc, Y, the Lanthanides, the Actinides,Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Tc, Re, Fe, Ru, Os, Co, Rh, Ir,Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, and Hg metal atoms and ions. Preferably,M¹ and M² are the same or different and are selected from the groupconsisting of zero-valent Rh, zero-valent Ru, zero-valent Mo,zero-valent Pd, and zero-valent Re. More preferably, each of M¹ and M²are Rh.

Z² and Z³, independently, are the atoms necessary to complete a 3-12membered heterocyclic ring. Examples of such atoms include, for example:substituted or, preferably, unsubstituted alkylene moieties, such asthose having the formula —(CH₂)_(i)—, where i is an integer from 1 to 8;and moieties having the formula —(CH₂)_(i)—X—(CH₂)_(j)—, where i and jeach independently represent integers from 0 to 4 and X is a heteroatom,such as O, S, and NR⁷⁰, where R⁷⁰ is a substituted or unsubstitutedalkyl, aryl, or heteroaryl group. Preferably, Z² and Z³ are the same,and, more preferably, each of Z² and Z³ have the formula —CH₂CH₂—.

Z¹ is an alkylene or arylene group. Illustratively, Z¹ can have theformula —(CH₂)_(i)—, where i is an integer from 1 to 8. Alternatively,Z¹ can have the formula —(CH₂)_(i)—X—(CH₂)_(j)—, where i and j eachindependently represent integers from 0 to 4 and X is a heteroatom, suchas O, S, and NR⁷⁰, where R⁷⁰ is an alkyl or aryl group. Stillalternatively, Z¹ can be a cycloalkyl moiety, such as cyclopent-1,3-diyland cyclohex-1,3-diyl, which can be substituted or unsubstituted. Stillalternatively, Z¹ can be an arylene moiety, such as a 1,3-phenylene or1,3-naphthylene, or an heterocyclic moiety, such as a pyrid-3,5-diyl,pyrid-2,6-diyl, 2H-pyran-3,5-diyl, and tetrohydropyran-3,5-diyl moiety.Preferably, Z¹ is a 1,3-phenylene moiety.

Q¹ and Q² are the same or different and are electron withdrawing groups.Examples of Q¹, suitable for use in the practice of the presentinvention are moieties having the formulae —C(O)R¹, —SO₂R¹, and—P(O)R¹R^(1′), and examples of suitable Q² include moieties having theformulae —C(O)R², —SO₂R², and —P(O)R²R^(2′). In these formulae, each ofR¹, R^(1′), R², and R^(2′) is independently selected from an alkylgroup, an aryl group, and an alkoxy group. Preferably, Q¹ has theformula —SO₂R¹; Q² has the formula —SO₂R²; and R¹ and R² are the same ordifferent and are substituted or unsubstituted alkyl or aryl groups.More preferably, Q¹ has the formula —SO₂R¹; Q² has the formula —SO₂R²;and each of R¹ and R² is independently selected from the groupconsisting of 4-(t-butyl)phenyl, 2,4,6-trimethylphenyl, and2,4,6-triisopropylphenyl.

In the above Formula II, L¹ and L³, taken together, represent a—O—CR¹³—O— moiety, and L² and L⁴, taken together, represent a —O—CR¹⁴—O—moiety. In these moieties, R¹³ and R¹⁴ can be the same or they can bedifferent, and each is independently selected from the group consistingof alkyl groups and aryl groups. Alternatively, R¹³ and R¹⁴ canrepresent alkylene or arylene groups that are directly or indirectlybonded to one another. In the latter case, the compound of the presentinvention can be expressed as the following formula (“Formula III”):

where R⁷² represents an alkylene or arylene group. Preferably, R¹³ andR¹⁴, taken together, represent an alkylene or arylene group such thatthe compound of the present invention has the following formula(“Formula IV”)

The above-described compounds have at least four chiral centers (i.e.,at least the two carbons to which Z² is bonded and at least the twocarbons to which Z³ is bonded are chiral). The present invention is notmeant to be limited to any particular set of configurations at thecompound's chiral centers, and the structures given above are meant tobe broadly read to include any and all possible collections ofchiralities. For example, compounds having Formula I are meant toinclude (i) compounds having the formula (“Formula V”):

and (ii) compounds having the formula (“Formula VI”):

Each of the compounds having Formulae V and VI can be present alone(i.e., as a pure diastereoisomer) or they can be present in a mixturewith one or more different diastereoisomers. Preferably, the compound issubstantially free of other diastereoisomers. In this context,“substantially free of other disatereoisomers” means that the molarratio of other diastereoisomers to the compound is less than 40%,preferably less than 30%, more preferably less that 20%, still morepreferably less that 10%, still more preferably less that 5%, still morepreferably less that 2%, and still more preferably less that 1%.

Preferred examples of compounds having Formula V and VI, respectively,are those having the formula (“Formula VII”):

and those having the formula (“Formula VIII”):

More preferred examples of compounds having Formula V and VI,respectively, are those having the formula (“Formula IX”):

and those having the formula (“Formula X”):

In Formula IX and Formula X, R¹ and R² are the same or different and arealkyl or aryl groups.

Compounds of the present invention can be made by a variety of methods.One particularly suitable method, which is the subject of another aspectof the. present invention, is illustrated below.

Compounds having Formula II can be prepared from ligands having theformula (“Formula XI”):

from ligands having the formula (“Formula XII”)

or from combinations of these ligands. In each of these formulae, R³ andR⁴ is independently selected from the group consisting of hydrogen, analkyl group, or an aryl group, and each of A¹ and A² is independentlyselected from the group consisting of a hydrogen atom and an electronwithdrawing group. Preferred ligands are those in which R³ and R⁴ areboth hydrogen atoms. However, ligands containing other groups in the R³and R⁴ positions can be employed, for example, by replacing these groupswith hydrogen atoms using, for example, conventional ester hydrolysismethods, such as room temperature saponification with a strong base(e.g., lithium hydroxide). Preferred ligands are those in which A¹ andA² are both electron withdrawing groups, such as —C(O)R², —SO₂R², or—P(O)R²R^(2′) groups where each of R¹, R^(1′), R², and R^(2′) is,independently, an alkyl group, an aryl group, or an alkoxy group.However, ligands in which one or both A¹ and A² are hydrogen atoms canbe used, for example, by replacing the hydrogen atoms with electronwithdrawing groups using, for example, conventional acylation,sulfonation, or phosphonylation procedures.

The ligands are converted to the compound of Formula II using abis-metal salt under conditions effective to produce the compound ofFormula II. Suitable bis-metal salts are those having the formulaM¹M²(OOCR⁵)₄ in which R⁵ is an alkyl group or an aryl group and in whichM¹ and M² are as defined above. Preferably, M¹ and M² are the same, andeach of the R¹ groups is a C1-C6 alkyl. More preferably, each of M¹ andM² is Rh, and each of the OOCR⁵ groups represents an acetate group, inwhich case the bis-metal salt has the formula Rh₂(OOCCH₃)₄.

The aforementioned conversion can be advantageously carried out bycontacting the bis-metal salt with the ligand for a period of time andat a temperature effective to produce the compound of Formula II. Thiscan be done, for example by pre-forming the bis-metal salt and thencontacting the preformed bis-metal salt with the ligand. Alternatively,the bis-metal salt can be produced in situ, for example, from anappropriate metal salt. This latter method is particularly advantageousin the case where M¹ and M² are the same. For example, in the case whereboth M¹ and M² are Rh, the method can be carried out by mixing theligand with rhodium diacetate rather than with the preformed dirhodiumtetraacetate. Irrespective of whether the bis-metal salt is preformed orpermitted to form in situ, the reaction is typically carried out in ansuitable solvent (e.g., an aromatic solvent, such as benzene, toluene,xylenes, or, preferably, a chlorinated benzene, such as chlorobenzene ordichlorobenzene, or a hydrocarbon solvent, such as hexanes, heptane,iso-octane, or n-octane), with stirring, under reflux, and/or with someother type or agitation, for from about 2 hours to about 10 days,preferably from about 1 day to about 5 days, and at a temperature offrom about 30° C. to about 150° C., preferably from about 120° C. toabout 140° C. Preferably, the reaction solvent is chosen so as to permitthe reaction to be carried out at a reflux temperature of from about120° C. to about 140° C. Furthermore, preferably, the reaction iscarried out in the presence of a compound capable of neutralizing acids.Where the reaction is carried out under reflux, this can beadvantageously achieved by refluxing the solvent through a soxhletextraction apparatus containing calcium carbonate or anotheracid-neutralizing compound. The resulting product can be separated fromthe reaction mixture by conventional means (e.g., by precipitation andfiltering and/or by removing the solvent, preferably under vacuum), andit can be optionally purified, for example, by crystallization orchromatorgraphy.

The ligands used in the above procedure can be produced using a numberof methods. Illustratively, N-substituted ligands having the formula(“Formula XIII”):

in which A³ and A⁴ are independently selected from the group consistingof —C(O)R², —SO₂R², and —P(O)R²R^(2′) and in which Z¹, Z², Z³, R¹,R^(1′), R², R^(2′), R³, and R⁴ are defined as they were above in thediscussion relating to Formulae XI and XII, can be produced by thefollowing method. The method includes providing an N-unsubstitutedcompound having the formula (“Formula XIV”):

wherein each of R⁶ and R⁷ is independently selected from an alkyl groupor an aryl group, and converting the N-unsubstituted compound to theN-substituted compound with an acylating agent, a sulfonylating agent,or a phosphonylating agent. Examples of suitable sulfonating agentsinclude arylsulfonyl chlorides, such as benzenesulfonyl chloride,4-methylbenzenesulfonyl chloride, and 2,4,6-triisopropylbenzenesulfonylchloride. Typically this conversion is carried out by contacting atleast two equivalents, preferably from about 2.3 to about 4 equivalents,of acylating agent, sulfonylating agent, or phosphonylating agent withthe N-unsubstituted compound at a temperature of from about 10° C. to100° C., preferably at about room temperature, for from about 15 minutesto about 10 days, preferably for from about 3 hours to about 5 days. Thereaction can be carried out neat (i.e., without the use of solvent), orit can be carried out in a suitable inert solvent, such an aromaticsolvent (e.g., benzene and toluene), an alkane solvent (e.g., hexanes),a chlorinated solvent (e.g., chlorobenzene or chloroform), or a ketonesolvent (e.g., acetone). In some cases, the reaction can be quitevigorous and may benefit from slow addition (e.g., dropwise addition) ofthe acylating agent, sulfonylating agent, or phosphonylating agent tothe N-unsubstituted compound while cooling the reaction mixture, withfor example, an ice-water bath. Typically, these reactions producestrong acid, which is advantageously neutalized. Neutralization can becarried out by carrying out the reaction in the presence of, forexample, an alkali metal carbonate or bicarbonate and/or by washing thereaction mixture with, for example, alkali metal carbonate orbicarbonate. The N-substituted compound can be separated from thereaction mixture by, for example, extraction, precipitation, and/orfiltration, and the N-substituted compound, thus separated, can bepurified by standard methods, such as recrystallization orchromatography. The method discussed above above for the preparation ofcompounds having Formula XIII can be readily adapted to preparesubstantially diasteriomerically pure compounds having Formula XI andFormula XII by using, respectively, N-unsubstituted compounds having theformula (“Formula XV”):

and having the formula (“Formula XVI”):

N-unsubstituted compounds having Formula XIV can be advantageouslyprepared by the following method, to which the present invention alsorelates. The method includes providing an unsaturated heterocycliccompound having the formula (“Formula XVII”):

and converting the unsaturated heterocyclic compound to theN-unsubstituted compound using hydrogenation. Typically, thehydrogenation reaction is carried out by contacting the unsaturatedheterocyclic compound with a hydrogenating agent, such as hydrogen gas,in the presence of a hydrogenation catalyst, for a suitable length oftime (e.g., from about 30 minutes to about 48 hours), at a suitabletemperature (e.g. from about 10° C. to about 100° C., preferably atabout room temperature), at a suitable pressure (e.g., from-aboutatmospheric pressure to about 100 psi), and in a suitable solvent (e.g.,ether solvents, such as tetrahydrofuran or diethyl ether; alkanesolvents, such as hexanes; aromatic solvents, such as benzene ortoluene; and alcohol solvents, such as ethanol or isopropanol). It hasbeen found that platinum oxide (e.g., PtO₂) is a particularly effectivecatalyst for this reaction, although other hydrogenation catalysts, suchas those described in Larock in Comprehensive Organic Transformations,New York: Wiley-VCH (1999) (“Larock”), particularly at pp. 7-12, whichis hereby incorporated by reference, can be used. Following thereaction, the N-unsubstituted compound is typically separated fromcatalyst by filtration, and the solvent is then removed, for example,under reduced pressure. Further purification of the resultingN-unsubstituted compound can be carried out by, for example,recrystallization or chromatography. Using the methods set forth above,N-unsubstituted compounds having Formula XV and Formula XVI can beprepared, respectively, from unsaturated heterocyclic compounds havingthe formula (“Formula XVIII”):

and having the formula (“Formula XIX”):

where Z¹, Z², Z³, R³, R⁴, R⁶, and R⁷ have the meanings set forth above.Preferred unsaturated heterocyclic compounds are those in which Z¹ is a1,3-phenylene group.

In some situations, it is particularly desirable to convert the estergroups (represented by COOR⁶ and COOR⁷)to the corresponding acid groups(represented by COOR³ and COOR⁴)prior to converting the N-unsubstitutedcompound to the N-substituted compound. As indicated above, this can bedone by conventional deesterification methods, such as for example,saponification. Such saponification can advantageously be carried out onthe crude N-unsubstituted compound resulting from the above-describedhydrogenation procedure. One suitable saponification method is to refluxthe N-unsubstituted compound with an excess of strong alkali metal basein water or a water/solvent mixture. For example, the N-unsubstitutedcompound can be dissolved and/or suspended in a mixture oftetrahydrofuran, ethanol, and water containing from about a 5 to about a100 molar excess of lithium hydroxide, and the resulting mixture can bestirred at room temperature or heated, preferably at reflux, for fromabout 2 hours to about 72 hours. The progress of this reaction can bemonitored, for example, by thin layer chromatography to determine whensaponification has reached the desired level of completion.

Unsaturated heterocyclic compounds having Formula XVII can beadvantageously prepared using the following method, to which the presentinvention also pertains. In this method, a cyclic ketone having theformula (“Formula XX”):

where R⁸ is an amine-protecting group, is converted to the N-unsaturatedheterocyclic compound with a bis-lithium compound having the formulaZ¹Li₂. For example, in the case where Z¹ is a 1,3-phenylene moiety, thebis-lithium compound used in this reaction is 1,3-dilithiobenzene.

“Amine protecting group”, as used herein refers to any group known inthe art of organic synthesis for the protection of amine groups.Suitable amine protecting groups are listed in Greene et al., ProtectiveGroups in Organic Synthesis, New York: John Wiley & Sons (1991), whichis hereby incorporated by reference. Examples of amine protecting groupsinclude, but are not limited to, acyl type amine protecting groups, suchas formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; aromaticcarbamate type amine protecting groups, such as benzyloxycarbonyl andsubstituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxy-carbonyl,and 9-fluorenylmethyloxycarbonyl; aliphatic carbamate type amineprotecting groups, such as tert-butyloxycarbonyl (“BOC”),ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; cyclicalkyl carbamate type amine protecting groups, such ascyclopentyloxycarbonyl and adamantyloxycarbonyl; alkyl type amineprotecting groups, such as triphenylmethyl (i.e., trityl) and benzyl;trialkylsilane type amine protecting groups, such as trimethylsilane;and thiol containing type amine protecting groups, such asphenylthiocarbonyl and dithiasuccinoyl. BOC is the preferred amineprotecting group.

The reaction of the cyclic ketone with the bis-lithium compound ispreferably carried out using conventional lithium alkylation procedures.Typically the reaction is carried out in an inert solvent (e.g.,tetrahydrofuran or diethyl ether) and in the strict absence of water byslowly adding (e.g., over the course of from about 30 minutes to about 2hours) an excess (e.g., from about 2 to about 10 equivalents) of thecyclic ketone (preferably dissolved in inert solvent) to the dilithiumcompound (preferably also dissolved in the inert solvent) at reducedtemperatures (e.g., from about 0° C. to about −78° C.). The resultingmixture is then typically permitted to warm to room temperature, withstirring, and stirring is continued for from about 2 hours to about 4days, preferably from about 15 hours to about 30 hours. After thereaction is complete, the mixture is typically poured into water andextracted with an organic solvent (e.g., ethyl acetate). The organicsolvent is dried (e.g., over MgSO₄) and removed, advantageously underreduced pressure.

The amine protecting group can then be cleaved using conventionalmethods, such as, in the case where the amine protecting group is BOC,by treating the reaction product with an excess (e.g., from about 20 toabout 100 equivalents, based on the amount of dilithium compoundemployed) of trifluoroacetic acid (“TFA”). This treatment is typicallycarried out in a suitable solvent (e.g., a chlorinated hydrocarbon, suchas dicloromethane or chloroform) for from about 30 minutes to about 48hours at from about 10° C. to about 100° C., preferably at about roomtemperature. Subsequently, the excess acid is neutralized (e.g., withbicarbonate), the solvent is removed (e.g., under reduced pressure), andthe unsaturated heterocyclic compound is optionally further purified(e.g., by recrystallization and/or chromatography).

Many suitable dilithium compounds can be purchased commercially.Alternatively, these compounds can be prepared by conventional methods,such as those set forth in Fossatelli et al., “1,3-Dilithiobenzene and1,4-Dilithiobenzene,” Rec. Trav. Chim. Pays-Bas, 113:527-528 (1994),which is hereby incorporated by reference.

Cyclic ketones that can be used to prepare the unsaturated heterocycliccompound, as described above, can. be obtained from commercial sources,or, alternatively, they can be produced, for example, using the methodsdescribed in, for example, Ezquerra et al., “Stereoselective Reactionsof Lithium Enolates Derived From N-BOC Protected Pyroglutamic Esters,”Tetrahedron, 49:8665-8678 (1993), which is hereby incorporated byreference.

In the case where the N-unsaturated heterocyclic compound has FormulaXVIII, it is advantageous to employ a cyclic ketone having the formula(“Formula XXI”):

In the case where the N-unsaturated heterocyclic compound has FormulaXIX, it is advantageous to employ a cyclic ketone having the formula(“Formula XXII”):

The above compounds (e.g., those represented by Formulae II, III, IV, V,VI, VII, VIII, IX, and X as well as those containing the moiety denotedFormula I) can be used to effect a variety of organic transformations.One such illustrative organic transformation is the C—H insertionreaction, such as those C—H insertion reactions in which bis-transitionmetal catalysts have been previously employed, especially in cases wheresubstantially diasteriomerically pure products are desired. Several ofsuch C—H insertion reactions are described below. However, nothingherein should be construed as meaning that the reactions described belowmust be carried out with the compounds described above.

The present invention further relates to a method of producing acompound having the formula (“Formula XXIII”):

R¹, R², and R³ are independently selected from H, alkyl, aryl, or vinyl,or R¹ and R³, together with the atoms to which they are bonded, form a5-12 membered ring, such as a cyclohexene ring, or a cyclohexa-1,3-dienering. The method is particularly well-suited for preparing compounds inwhich R¹ and R³, together with the atoms to which they are bonded, forman aromatic ring, such as a phenyl ring, in which case the compoundproduced by this method has the formula (“Formula XXIV”):

Y is an electron withdrawing group, examples of which include moietieshaving the formulae: —C(O)R⁷⁷, —SO₂R⁷⁷, and —P(O)R⁷⁷R^(77′). In theseformulae, each of R⁷⁷ and R^(77′) is independently selected from analkyl group, an aryl group, and an alkoxy group. Preferably, Y has theformula CO₂R¹² where R¹² is an alkyl group or an aryl group.

X is CH₂, O, or NR¹¹, and R¹¹ is H, an alkyl group, an aryl group, anacyl group, an alkoxycarbonyl group, or a silyl group having the formula—SiR³³R³⁴R³⁵, where R³³, R³⁴, and R³⁵ are independently selected from analkyl group and an aryl group.

Each of R³⁰ and R³¹ is independently selected from the group consistingof H, alkyl, aryl, and vinyl. R³² is an alkyl group, an aryl group, anacyl group, an alkoxycarbonyl group, or a silyl group having the formula—SiR³⁶R³⁷R³⁸, where R³⁶, R³⁷, and R³⁸ are independently selected from analkyl group and an aryl group. Alternatively, R³¹ and R³², together withthe atoms to which they are bonded, can form a 5-12 membered ring, suchas a cyclopentyl or cyclohexyl ring (in the case where X is —CH₂—), apiperidinyl ring (in the case where X is N), or a tetrahydrofuranyl or atetrahydropyranyl ring (in the case where X is O). Illustratively, themethod of the present invention is well-suited for forming compoundshaving Formula XXIV in which X is not CH₂ when each of R³⁰ and R³¹ is H.

The method includes providing a diazo compound having the formula(“Formula XXV”):

in which R¹, R², R³, and Y have the same meanings as given above withreference to Formula XXIV. The method further includes converting thediazo compound with a compound having the formula (“Formula XXVI”):

in the presence of a bis-transition metal catalyst and under conditionseffective to produce the compound. In compound XXVI, R³⁰, R³¹, and R³²are defined as they are above with regard to Formula XXIV. When, in thedesired product, X is CH₂ or O, X′ in Formula XXVI is CH₂ or O,respectively. When, in the desired product, X is NR¹¹, X′ in FormulaXXII is NR^(11′) and R^(11′) is an alkyl group, an aryl group, an acylgroup, an alkoxycarbonyl group, or a silyl group (e.g., a triarylsilylgroup, or a trialkylsilyl group). It is particularly preferred that,when X′ represents an NR^(11′) group, R^(11′) represents analkoxycarbonyl amine protecting group, such as BOC.

Suitable bis-transition metal catalysts for use in this reactioninclude, for example, catalysts having the formula L₄M—ML₄ where each ofthe L's is the same or different and represents a suitable ligand (e.g.,an oxygen from an acetate moiety) and each of the M's is the same ordifferent and represents a transition metal (e.g., Rh or Ru). Dirhodiumand diruthenium catalysts, especially dirhodium or dirutheniumtetracarboxylate catalysts, are preferred.

Illustrative dirhodium or diruthenium tetracarboxylate catalysts arethose having the formula (“Formula XXVII”):

In Formula XXVII, each of M¹ and M² is Rh or Ru. Z⁴ represents the atomsnecessary to complete a 3-12 membered heterocyclic ring, such as analkylene moiety (e.g., a —CH₂CH₂CH₂— moiety). Q³ is an electronwithdrawing group, such as a group having the formulae —C(O)R⁹, —SO₂R⁹,or —P(O)R⁹R⁹, where each of R⁹ and R^(9′) is independently selected froman alkyl group, an aryl group, and an alkoxy group. In cases where thedesired product of Formula XXIII is substantially diasteriomericallypure, it is advantageous to use a substantially chirally pure catalyst,such as a dirhodium or diruthenium tetracarboxylate catalyst having theformula (“Formula XXVIII”):

More preferably, the dirhodium or diruthenium tetracarboxylate catalysthaving Formula XXVIII has D₂ symmetry.

Specific examples of suitable compounds having Formulae XXVII and XXVIIIinclude: Rh₂(DOSP)₄, which is a compound having Formula XXVII in whicheach of M¹ and M² is Rh, Z⁴ is a —CH₂CH₂CH₂— group, and Q³ represents a4-dodecylphenylsulfonyl moiety; Rh₂(S-DOSP)₄, which is a compound havingFormula XXVIII in which each of M¹ and M² is Rh, Z⁴ is a —CH₂CH₂CH₂—group, and Q³ represents a 4-dodecylphenylsulfonyl moiety; Rh₂(TBSP)₄,which is a compound having Formula XXVII in which each of M¹ and M² isRh, Z⁴ is a —CH₂CH₂CH₂— group, and Q³ represents a4-t-butylphenylsulfonyl moiety; and Rh₂(S-TBSP)₄, which is a compoundhaving Formula XXVIII in which each of M¹ and M² is Rh, Z⁴ is a—CH₂CH₂CH₂— group, and Q³ represents a 4-t-butylphenylsulfonyl moiety.These and other illustrative compounds having Formulae XXVII and XXVIIIare described in greater detail in Davies, “Rhodium-StabilizedVinylcarbenoid Intermediates in Organic Synthesis,” Current OrganicChemistry, 2:463-488 (1998) (“Davies”), which is hereby incorporated byreference.

Particularly suitable bis-transition metal catalysts for carrying outthe conversion of XXV with XXVI are those having Formulae II, III, IV,V, VI, VII, VIII, IX, and X, as defined and discussed above,particularly where M¹ and M² are Rh or Ru. Other particularly suitablebis-transition metal catalysts for carrying out the conversion of XXVwith XXVI are chiral dirhodium or diruthenium catalysts, especiallythose which include a first metal atom and a second metal atom that arebonded to one another along an axis and two carboxylate ligands. Each ofthe two carboxylate ligands includes two carboxylate groups bonded toeach other via a moiety having Formula I. Each of the two carboxylategroups includes a first carboxylate oxygen atom (“O¹”), a secondcarboxylate oxygen atom (“O²”), and a carbon (“C”) to which the O¹ andthe O² are bonded thereby forming two O¹—C—O² moieties, and each O¹—C—O²moiety defines a plane which is substantially parallel to the axis. O¹of each of the two carboxylate groups of each of the two carboxylateligands is bonded to the first metal atom; O² of each of the twocarboxylate groups of each of the two carboxylate ligands is bonded tothe second metal atom; each of the two carboxylate ligands furthercomprises at least two chiral centers; and the compound has D₂ symmetry.Such bis-transition metal catalysts are discussed in greater detailabove.

Typically, the reaction is carried out by mixing the catalyst with thecompound of Formula XXVI. In the case where the compound of Formula XXVIis a liquid (e.g., in the case where the compound of Formula XXVI istetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, cyclopentane,cyclohexane, etc.), this can be effected without the use of additionalsolvent. Alternatively, the mixture can be formed using an inert solventor a solvent which is significantly less reactive toward the diazocompound of Formula XXV than is the compound of Formula XXVI. As anexample, it has been found that when the compound of Formula XXVI istetrahydrofuran, the catalyst and tetrahydrofuran can be mixed neat(i.e., without the use of additional solvent), or cyclohexane can beused as a reaction medium. The amount of catalyst employed is notcritical to the practice of the present invention. Typically, the moleratio of the catalyst to the compound of Formula XXVI is from about1:10,000 to about 1:20, preferably from about 1:500 to about 1:50, andmore preferably from about 1:200 to about 1:100.

Once the catalyst and compound of Formula XXVI are mixed, the diazocompound of Formula XXV is added, preferably with stirring. Addition canbe carried out in a single portion, continuously, or batchwise. Slow,dropwise addition, using, for example, a syringe pump, is frequentlyadvantageous. The amount of diazo compound of Formula XXV added isgenerally dependent on the amount of the compound of Formula XXVIpresent in the reaction mixture. Typically the mole ratio of thecompound of Formula XXVI to the diazo compound of Formula XXV is fromabout 1:10 to about 10:1, preferably from about 6:1 to about 1:1, morepreferably from about 4:1 to about 2:1. The addition can be carried outat any suitable temperature from the freezing point to the boiling pointof the solvent and/or the compound of Formula XXVI. Typically, theaddition is carried out from about −50° C. to about 60° C. Roomtemperature addition and addition at about 10° C. have been found to beadvantageous. Optimization of reaction conditions, including temperatureof addition, is more important when diastereomerically pure product isdesired. Generally, formation of diastereomerically pure product isfavored by lower addition temperatures (e.g., from about −50° C. toabout 10° C.).

Applicants have unexpectedly discovered that, when the reaction of thepresent invention is carried out substantially in the absence of oxygen,the resulting product has significantly improved yield when compared toreactions which are not carried out substantially in the absence ofoxygen. As used herein, “substantially in the absence of oxygen” meansthat the liquid reactants and solvents (if any) employed in carrying outthe reaction are degassed, for example by bubbling an inert gas (e.g.,nitrogen or argon) therethrough, that the reaction is carried out underblanket of inert gas or under vacuum, and that all transfers are carriedout such that ambient air is excluded (e.g., by using rubber septums,gas tight syringes, and the like). Illustratively, applicants haveunexpectedly discovered that when X is O or CH₂, when R¹ and R³,together with the atoms to which they are bonded, form a 5-12 memberedring, and when R³¹ and R³², together with the atoms to which they arebonded, form a 5-12 membered ring, carrying out the reactionsubstantially in the absence of oxygen produces a product havingsignificantly improved diastereoisomeric purity. When carrying out thesereactions substantially in the absence of oxygen, it is advantageous touse a chiral catalyst, preferably a chiral catalyst having D₂ symmetry.

The conversion of the compound of Formula XXV with a compound of FormulaXXVI to produce a compound of Formula XXIII described above isparticularly suitable for preparing compounds having the formula(“Formula XXIX”):

In this case, the conversion of the diazo compound of Formula XXV iscarried out with a cyclic compound having the formula (“Formula XXX”):

in which X′ is defined as above and n is 3-10. In this embodiment, R¹and R³, together with the atoms to which they are bonded, preferablyform a phenyl ring, and Y preferably has the formula —CO₂R¹⁰ where R¹⁰is an alkyl or aryl group. The method is particularly suitable formaking compounds in which X is NR¹¹ and in which n is 3 or 4. The methodis also particularly suitable for making compounds having the formula(“Formula XXXI”):

in which case the bis-transition metal catalyst employed is a chiralbis-transition metal catalyst. For example, by using the S-isomer ofcompounds having Formulae II, III, IV, V, VI, VII, VIII, IX, or X, asdefined and discussed above (particularly where M¹ and M² are Rh or Ru),compounds of Formula XXXI which are substantially diasteriomericallypure (e.g., >80% ee, >90% ee, >95% ee, >98% ee, and/or >99% ee) can beprepared. Particularly preferred compounds having Formula XXXI are thosein which X is NR¹¹, n is 3, Y is CO₂R¹², R¹² is alkyl or aryl, and R¹and R³, together with the atoms to which they are bonded, form anaromatic ring. Still more preferred are those compounds of Formula XXXIin which X is NH, R¹² is a methyl group, and R¹ and R³, together withthe atoms to which they are bonded, form a phenyl ring. Such compoundshave the formula (“Formula XXXII”):

which is also referred to as threo methylphenidate and which is believedto be the biologically active form of RITALIN™.

The method of the present invention can also be used to preparedcompounds having Formula XXIII in which X is NR¹¹ and in which R³¹ andR³², together with the atoms to which they are bonded represent a ringhaving the formula (“Formula XXXIII”):

where R³⁰ is H. That is, the method can be used to prepare compoundshaving the formula (“Formula XXXIV”):

In these formulae, R⁴¹, R⁴², and R⁴³ are independently selected from H,alkyl, aryl, or vinyl, or R⁴¹ and R⁴³, together with the atoms to whichthey are bonded, form a 5-12 membered ring. Y′ is an electronwithdrawing group, for example, the electron withdrawing groupsdiscussed above with regard to Y, and m is 2-9. The reaction involvesproviding a diazo compound having Formula XXV and converting the diazocompound with a cyclic amine having the formula (“Formula XXXV”):

in the presence of a bis-transition metal catalyst and under conditionseffective to produce the compound. Suitable conditions for this reactionare the same as the ones discussed above with regard to the conversionof compounds of Formula XXV with compounds of Formula XXVI. By using achiral catalyst, compounds having the formula (“Formula XXXVI”):

can be produced.

A variety of methods can be used to prepare the cyclic amine havingFormula XXXV, but the preferred method is the one described above withregard to preparing compounds having Formula XXIX using diazo compoundsof Formula XXV, cyclic compounds of Formula XXX, and a bis-transitionmetal catalyst. Rather than running the reaction in two steps (i.e., byfirst reacting a diazo compounds of Formula XXV with a cyclic compoundof Formula XXX in which X is N to produce a cyclic amine having FormulaXXIX and then reacting the cyclic amine having Formula XXIX with a diazocompound having Formula XXV to produce the desired compound of FormulaXXXIV), the reaction can be carried out in a single step by, forexample, contacting the cyclic compound of Formula XXX in which X is Nwith at least two equivalents of a diazo compound of Formula XXV. Thereaction conditions suitable for carrying out this one step reaction arethe same as those discussed above with regard to the two step method.Preferably, during the first part of the reaction (i.e., during theaddition of the first half of the diazo compound having Formula XXV),the reaction is carried out with cooling (e.g., from about −50° C. toabout 0° C.). Then the reaction mixture is warmed, and the second partof the reaction (i.e., during the addition of the second half of thediazo compound having Formula XXV) is carried out at elevatedtemperatures (e.g., from about 20° C. to about 100°0 C.). Alkanes havingmelting points of less than about −50° C. and boiling points greaterthan about 60° C. are the preferred solvents for this reaction.

The compounds prepared by the above method (i.e., compounds havingFormulae XXIII, XXIV, XXIX, XXXI, XXXII, XXXIV, and XXXVI) areappropriately functionalized for further conversion by, for example,ester reduction or Grignard addition to highly functionalized bases. Inthe case where a chiral catalyst is employed, e.g., the S-isomer ofcompounds having Formulae II, III, IV, V, VI, VII, VIII, IX, or X, asdefined and discussed above (particularly where M¹ and M² are Rh or Ru),these compounds can be used as C₂ symmetric bases, or, as indicatedabove, they can be further converted (e.g., by ester reduction orGrignard addition) to highly functionalized C₂ bases. C₂ bases are veryuseful for controlling stereochemistry in organic synthesis, forexample, as described in Takahata et al., “New Entry to C2 SymmetricTrans-2,6-bis(hydroxymethyl)piperidine Derivatives Via the SharplessAsymmetric Dihydroxylation,” Tetrahedron-Asymmetry, 6:1085-1088 (1995)and in Bennani et al., “Trans-1,2-diaminocyclohexane Derivatives asChiral Reagents, Scaffolds, and Ligands for Catalysis—Applications inAsymmetric Synthesis and Molecular Recognition,” Chemical Reviews,97:3161-3195 (1997), which are hereby incorporated by reference.

The present invention also relates to a method for making a compoundhaving the formula (“Formula XXXVII”):

In Formula XXXVII, R¹, R², and R³ are independently selected from H,alkyl, aryl, or vinyl, or R¹ and R³, together with the atoms to whichthey are bonded, form a 5-12 membered ring, such as a cyclohexene ring,or a cyclohexa-1,3-diene ring. The method is particularly well-suitedfor preparing compounds in which R¹ and R³, together with the atoms towhich they are bonded, form an aromatic ring, such as a3,4-dichlorophenyl ring, in which case the compound produced has theformula (“Formula XXXVIII”):

Y is an electron withdrawing group, examples of which include moietieshaving the formulae: —C(O)R⁷⁷, —SO₂R⁷⁷, and —P(O)R⁷⁷R^(77′). In theseformulae, each of R⁷⁷ and R^(77′) is independently selected from analkyl group, an aryl group, and an alkoxy group. Preferably, Y has theformula CO₂R¹² where R¹² is an alkyl group or an aryl group.

Each of R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, and R⁵⁹ is independently selected fromthe group consisting of H, alkyl, aryl, halogen, and alkoxy. Preferably,each of R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, and R⁵⁹ is hydrogen.

The method includes providing a 1,3-cyclohexadiene having the formula(“Formula XXXIX”):

where R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, and R⁵⁹ are defined as above. The methodfurther includes converting the 1,3-cyclohexadiene with a diazo compoundhaving the formula (“Formula XL”):

in which Y, R¹, R², and R³ are as defined above. The conversion iscarried out in the presence of a bis-transition metal catalyst and underconditions effective to produce the compound.

Suitable bis-transition metal catalysts include, for example, thosecatalysts set forth above with regard to the method of producingcompounds of Formula XXIII.

Typically, the reaction is carried out by mixing the catalyst with the1,3-cyclohexadiene of Formula XXXIX. In the case where the1,3-cyclohexadiene of Formula XXXIX is a liquid (e.g., in the case wherethe compound of Formula XXXIX is 1,3-cyclohexadiene), this can beeffected without the use of additional solvent. Alternatively, themixture can be formed using an inert solvent or a solvent which issignificantly less reactive towards the diazo compound of Formula XLthan is the compound of Formula XXXIX. Suitable solvents includealkanes, such as hexanes. The solvent is preferably dried prior to useusing conventional methods, and the reaction vessel is also preferablydried, such as by flaming or in an oven. The amount of catalyst employedis not critical to the practice of the present invention. Typically, themole ratio of catalyst to compound of Formula XXXIX is from about1:10,000 to about 1:20, preferably from about 1:1000 to about 1:100, andmore preferably from about 1:500 to about 1:700.

Once the catalyst and compound of Formula XXXIX are mixed, the compoundof Formula XL is added, preferably with stirring. Addition can becarried out in a single portion, continuously, or batchwise. Slow,dropwise addition using, for example, a syringe pump is frequentlyadvantageous. The amount of compound of Formula XL added is generallydependent on the amount of compound of Formula XXXIX present in thereaction mixture. Typically the mole ratio of compound of Formula XL tocompound of Formula XXXIX is from about 1:10 to about 10:1, preferablyfrom about 1:8 to about 1:1, more preferably from about 1:6 to about1:4. The addition can be carried out at any suitable temperature fromthe freezing point to the boiling point of the solvent and/or thecompound of Formula XXXIX. Typically, the addition is carried out fromabout −50° C. to about 60° C., preferably at about room temperature.Generally, higher temperatures favor an undesirable reverse Coperearrangement in which compounds having Formula XXXVII rearrange to formcompounds having the formula (“Formula XLI”):

The method is also particularly suitable for making compounds havingFormula XXXVII which are substantially diasteriomerically pure, such as,for example, compounds having the formula (“Formula XLII”):

such as compounds having the formula (“Formula XLIII”):

When a substantially diastereomerically selective reaction is desired,the use of a chiral catalyst, preferably one with D₂ symmetry, ispreferred. For example, by using the S-isomer of compounds havingFormulae II, III, IV, V, VI, VII, VIII, IX, and X, as defined anddiscussed above (particularly where M¹ and M² are Rh or Ru), compoundsof Formulae XLII and XLIII which are substantially diasteriomericallypure (e.g., >80% ee, >90% ee, >95% ee, >98% ee, and/or >99% ee) can beprepared.

The present invention also relates to methods for making compoundshaving the formula (“Formula XLIV”):

in which R¹, R², R³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁸, R⁵⁹, and Y are defined as theywere above for the compounds having Formula XXXVII.

The method includes providing a cyclohexadiene derivative having FormulaXXXVII wherein R⁵⁷ is H. Preferred cyclohexadiene derivatives which canbe used in this reaction are those described above, and they can beconveniently prepared using, for example, the methods disclosed above.Once the cyclohexadiene derivative is provided, it is converted withhydrogenating and oxidizing agents under conditions effective to formthe compound of Formula XLIV. The hydrogenation and oxidation reactionscan be carried out simultaneously or seuqentially, and, when carried outsequentially, hydrogenation can precede oxidation or oxidation canprecede hydrogenation. Suitable hydrogenating agents for use in thepresent reaction include hydrogen gas in combination with a metalcatalyst, such as palladium, preferably palladium on carbon. Othersuitable metal catalysts include those set forth in Larock, particularlyat pp. 7-12, which is hereby incorporated by reference. Suitableconditions for carrying out such reactions are described, for example,in Larock, particularly at pp. 7-12, and in House, Modern SyntheticReactions, 2nd ed., Menlo Park, Calif.: The Benjamin/Cummings PublishingCompany, pp. 1-34 (1972), which are hereby incorporated by reference.

Suitable oxidizing agents for use in the present reaction include thosewhich are generally known to dehydrogenate 1,4-cyclohexadienyl moietiesto phenyl moieties, such as 2,3-dicloro-5,6-dicyano-1,4-benzoquinone(“DDQ”) and tetrachlorobenzoquinone (a.k.a., chloranil). Other suitableoxidizing agents and suitable conditions for carrying out such reactionsare described, for example, in House, Modern Synthetic Reactions, 2nded., Menlo Park, Calif.: The Benjamin/Cummings Publishing Company, pp.34-44 (1972), and in Larock, particularly at p. 189, which are herebyincorporated by reference.

The above-described method is particularly useful for making compoundshaving Formula XLIV in which Y is an alkoxycarbonyl group (e.g., inwhich Y has the formula —COOR¹² and R¹² is an alkyl group) and/or inwhich R¹ and R³, together with the atoms to which they are bonded, forman aromatic ring, such as a 3,4-dichlorophenyl ring. In the latter case,the compound of Formula XLIV has the formula (“Formula XLV”):

Furthermore, by using a cyclohexadiene having Formula XLII (e.g., acyclohexadiene having Formula XLIII), substantially diasteriomericallypure compounds of Formula XLIV, such as those having the formula(“Formula XLVI”)

and, more particularly, those having the formula (“Formula XLVII”):

can be prepared.

The present invention, in yet another embodiment thereof, relates to amethod for making for preparing a compound having the formula (“FormulaXLVIII”):

R¹, R², and R³ are independently selected from H, an alkyl group, anaryl group, or a vinyl group, or R¹ and R³, together with the atoms towhich they are bonded, form a 5-12 membered ring. Preferably, R¹ and R³,together with the atoms to which they are bonded, form an aromatic ring,such as a substituted or unsubstituted 1,3-phenylene ring. R⁵⁴, R⁵⁵,R⁵⁶, R⁵⁸, and R⁶⁵ are independently selected from the group consistingof H, alkyl groups, aryl groups, halogen, amino groups (which are meantto include amines that are unsubstituted or mono- or di-substitutedwith, for example, alkyl or aryl groups), alkoxy groups, hydroxy groups,and acid groups (which are meant to include, carboxylic and sulfonicfree acids, acid salts, acid esters, acid amides, and the like).Examples of such compounds include those in which each of R⁵⁴, R⁵⁵, andR⁵⁶ are H and R⁵⁸ is an amino group, such as an unsubstituted aminogroup. R⁶² represents an alkyl moiety, examples of which include methyl,ethyl, or propyl groups, which can optionally be substituted with, forexample, aryl groups (optionally containing a heteroatom) (e.g.,pyrid-4-ylmethyl) or amino groups (which are meant to include aminesthat are unsubstituted or mono- or di-substituted with, for example,alkyl or aryl groups) (e.g., 2-(N,N-diisopropylamino)ethyl).Alternatively, R⁶⁵ and R⁶² together represent the atoms necessary tocomplete a 5-12 membered, in which case the compound produced has theformula (“Formula XLIX”):

In this formula, Z⁶ represents, for example, an alkylene group (e.g., agroup having the formula —CH₂CH₂—, —CH₂CH₂CH₂, —CH(NH₂)CH₂CH₂—,—CH₂CH₂CH(NH₂)—, —CH₂NRCH₂—, —CH₂CH(C₆H₅)CH₂—, etc.). Specific compoundsof Formula XLVIII which can be made using this method include1,1-diarylalkanes, such as the pharmaceuticals tolterodine and CDP-840,which respectively have the formulae:

as well as nominfensine and sertraline, which respectively have theformulae:

The method includes providing a cyclohexadiene derivative having theformula (“Formula L”):

where R⁵⁷ is H, R⁵⁹ is selected from the group consisting of H, alkylgroups, aryl groups, halogens, amino groups, alkoxy groups, hydroxygroups, and acid groups, and Y is an electron withdrawing group. Thechoice of R⁵⁹ depends upon whether, in the intended product of FormulaXLVIII, R⁶⁵ represents an H, an alkyl group, an aryl group, a halogen,an amino group, an alkoxy group, a hydroxy group, or an acid group orwhether R⁶⁵ combines with R⁶² to represent a ring structure. In theformer case, R⁵⁹ is most conveniently selected so as to be the same asthe desired R⁶⁵ group. In the latter case, R⁵⁹ is chosen to be suitablyreactive with a cyclizing agent (e.g., R⁵⁹ can be hydrogen).Cyclohexadiene derivatives which can be used in this reaction are thosedescribed above, and they can be conveniently prepared using, forexample, the methods disclosed above.

Once the cyclohexadiene derivative having Formula L is provided, it isconverted with hydrogenating and oxidizing agents under conditionseffective to form a phenyl derivative having the formula (“Formula LI”):

The hydrogenation and oxidation reactions can be carried outsimultaneously or sequentially, and, when carried out sequentially,hydrogenation can precede oxidation or oxidation can precedehydrogenation. Suitable hydrogenating and oxidizing agents and methodsfor their use are described above with regard to to methods forpreparing compounds having Formula XLIV.

The phenyl derivative having Formula LI is then converted to thecompound having Formula XLVIII. Conditions effective for achieving thisconversion depends on the nature of the desired substituents at R⁶² andR⁶⁵. Generally, in the case where R⁶² and R⁶⁵ are discreet moieties(i.e., in the case where R⁶² and R⁶⁵ do not combine to form a ringstructure), R⁵⁹ will have been chosen so that no further chemistry isrequired at that position to obtain the desired R⁶⁵ substituent, and the—CH₂CH₂Y moiety can be converted to the desired R⁶² substituent usingconventional methods. In the case where R⁶² and R⁶⁵ combine to form aring, conventional cyclization chemistry can be employed. For example,in the case where R⁵⁹ is H and R⁶² and R⁶⁵ together represent a—CH₂CH₂CH₂— moiety, cyclization can be carried out using, for example, aFriedel-Crafts acylation catalyst, such as those described in Larock,particularly at pp. 1381-1403, which is. hereby incorporated byreference.

The above method for making compounds having Formula XLVIII isillustrated by the following procedure for making sertraline orsertraline congeners having the formula (“Formula LII”):

In Formula LII, R¹, R², R³, R⁵⁴, R⁵⁵, R⁵⁶, and R⁵⁸ are defined as theywere above with regard to compounds of Formula XXXVII. R⁶⁰ is H. R⁶¹ canrepresent a substituted or unsubstituted amine, such as an amine havingthe formula —NR⁶³R⁶⁴, where each of R⁶³ and R⁶⁴ is independentlyselected from hydrogen, an alkyl group, and an aryl group.Illustratively, R⁶¹ can be a dialkyl amino group (e.g., N(CH₃)₂), amonoalkylamino group (e.g., —NHCH₂CH₃), or a monoarylamino group (e.g.,—NH (C₆H₅)), or R⁶¹ can represent a cyclic amine moiety, such as apiperidinyl group or a morpholino group. Alternately, R⁶⁰ and R⁶¹,together with the carbon atom to which they are bonded, can represent acarbonyl (i.e., a C═O) moiety.

The method includes providing a cyclohexadiene derivative having FormulaXXXVII in which Y is an electron withdrawing group, such as any one ofthe electron-withdrawing groups described above, and R⁵⁷ and R⁵⁹ are H.Cyclohexadiene derivatives which can be used in this reaction are thosedescribed above. Once the cyclohexadiene derivative is provided, it isconverted with hydrogenating, oxidizing, and cyclizing agents underconditions effective to form the compound of Formula LII. Thehydrogenation and oxidation reactions can be carried out simultaneouslyor sequentially, and, when carried out sequentially, hydrogenation canprecede oxidation or oxidation can precede hydrogenation. Generally, itis desirable that both hydrogenation and oxidation precede cyclization,that is, that the cyclohexadiene derivative be converted with ahydrogenating agent and an oxidizing agent into a phenyl derivativehaving the formula (“Formula LIII”):

and that the phenyl derivative then be converted with a cyclizing agentunder conditions effective to produce the compound.

Suitable hydrogenating and oxidizing agents and methods for their useare described above with regard to to methods for preparing compoundshaving Formula XLIV. Cyclizing agents suitable for use in the practiceof the present invention include acylation catalysts, such as FriedelCrafts acylation catalysts, examples of which include ClSO₃H, AlCl₃, andother Lewis acids. In the case where Y is an alkoxycarbonyl group, itmay be advantageous to convert the alkoxy group to a hydroxy group,prior to treatment with the Friedel Crafts acylation catalyst. This canbe done using strong acid, e.g., 6 N HCl, or by any other suitablemethod. The immediate product of such a cyclization is a tetralonehaving the formula:

which can be readily converted to compounds having Formula LII bymethods known to those skilled in the art, such as the reductiveamination method set forth in Corey, which is hereby incorporated byreference.

The above-described method is particularly useful for making compoundshaving Formula LII in which Y is an alkoxycarbonyl group (e.g., in whichY has the formula —COOR¹² and R¹² is an alkyl group) and/or in which R¹and R³, together with the atoms to which they are bonded, form anaromatic ring, such as a 3,4-dichlorophenyl ring, in which case thecompound of Formula LII has the formula (“Formula LIV”):

Furthermore, by using a cyclohexadiene having Formula XLII (e.g., acyclohexadiene having Formula XLIII), substantially diasteriomericallypure compounds of Formula LII, such as those having the formula(“Formula LV”):

and, more particularly, those having the formula (“Formula LVI”):

can be prepared.

The present invention is further illustrated by the followingnon-limiting examples.

EXAMPLES Example 1

Synthetic Scheme for the Preparation of DirhodiumBis[bridged-di(S-2,4,6-triisopropylphenylsulfonylprolinate)]

Dirhodium bis[bridged-di(S-2,4,6-triisopropylphenylsulfonylprolinate)]was prepared using the following general reaction Scheme I, in which Rrepresents a 2,4,6-triisopropylphenyl group. Details for each step setforth in this scheme are described, below, in Examples 2-6.

Example 2

Preparation of Imine 2

To a −78° C. solution of 1,3-diiodobenzene (3.431 g, 10.4 mmol) in THF(100 ml) was added 1.7 M t-butyl lithium (25.1 ml, 42.6 mmol, 4.1equiv). The mixture was stirred at −78° C. for 0.5 hours and thenallowed to warm to room temperature over 1 hour. The mixture was thencooled to −78° C. again and then added to a −78° C. solution ofS-N-BOC-pyroglutamic ethylester (1) (13.62 g, 62.4 mmol, 6.0 equiv) inTHF (75 ml). The resulting mixture was stirred at −78° C. for 1 hour andthen stirred at room termperature for 20 hours. The reaction mixture waspoured into water (300 ml), and extracted with ethyl acetate. Theorganic layer was separated and dried with MgSO₄, and the solvent wasremoved to produce a residue.

The residue was dissolved in dichloromethane (60 ml). To this was addedTFA (48.1 ml, 0.624 mol), and the resulting mixture was stirred at roomtemperature for 20 hours. The solvent was then removed, and the residuewas redissolved in dichloromethane and then extracted four times withsaturated bicarbonate, twice with water, and then with brine. Theorganic layer was separated and dried with MgSO₄, and solvent wasremoved. The resulting residue was purified by chromatography on silicausing EtOAc/hexanes (5:4) to give 1.3827 g of imine 2 as an oil (37%):TLC R_(f) 0.33 (EtOAc/hexanes (70:30)); [α]²⁵D=109° (c 1.358, CHCl₃); IR(NaCl) 2981, 1738, 1623, 1576 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ8.31 (s,1H), 7.95 (d 2H), 7.43 (t, 1H), 4.88 (dd, 2H, J=7.6, 7.2 Hz), 4.21 (q,4H, J=7.6 Hz), 3.22-3.08 (m, 2H), 3.04-2.90 (m, 2H), 2.40-2.27 (m, 2H),2.27-2.13 (m, 2H), 1.29 (t, 6H, J=7.2 Hz); ¹³C NMR (75 MHz, CDCl₃)δ174.7, 171.9, 133.3, 129.5, 127.7, 126.7, 73.8, 60.1, 34.6, 25.6, 13.3.HRMS (EI) calcd for C₂₀H₂₄N₂O₄, 356.1736, found 356.1718.

Example 3

Preparation of Diamine 3

Imine 2 (2.4236 g, 6.80 mmol) was hydrogenated at 55 psi of H₂, withPtO₂ (6 mg/mmol of substrate) in ethanol (6 ml/mmol of substrate). Thereaction was agitated for 25 hours and then filtered through a plug ofcelite. The solvent was removed under reduced pressure, and the residuewas purified by chromatography on silica using EtOAc/hexanes (2:1 w/5%triethylamine) to give 2.196 g of diamine 3 as an oil (90%): TLC R_(f)0.31 (EtOAc/hexanes (2:1 w/5% triethylamine)); [α]²⁴D=11° (c 3.794,CHCl₃); IR (NaCl) 3356, 2983, 2908, 2876, 1742, 1731, 1609, 1454, 1380cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.45 (s, 1H), 7.40-7.25 (m, 3H),4.30-4.10 (m, 6H), 3.90 (dd, 2H, J=8.4, 8.1 Hz), 2.42 (s, 2H), 2.30-2.05(m, 6H), 1.92-1.60 (m, 2H), 1.30 (t, 6H, J=7.5 Hz); ¹³C NMR (75 MHz,CDCl₃) δ174.8, 143.2, 128.3, 125.2, 125.1, 63.2, 60.6. 59.7, 33.8, 30.2,13.9; HRMS (EI) calcd for C₁₇H₂₃N₂O₂(m-COOEt), 287.1757, found 287.1723.

Example 4

Preparation of Bridged di(ethylS-2,4,6-triiso-propylphenylsulfonylprolinate) 4

Diamine 3 (1.4 g, 3.95 mmol) and potassium carbonate (2.2 g, 15.8 mmol,4.0 equiv) were stirred in acetone (40 ml). Then,2,4,6-triisopropylbenzenesulfonyl chloride (3.6 g, 11.8 mmol, 3.0 equiv)was added. After the resulting reaction mixture was stirred for four (4)days at room temperature, a second portion of acetone (100 ml) wasadded. The mixture was filtered, and the solvent was removed underreduced pressure. The residue was purified by chromatography on silicausing EtOAc/hexanes (1:9) to give 2.1 g of bridged di(ethylS-2,4,6-triiso-propylphenylsulfonylprolinate) (“diTiPBSP-COOEt”) 4 as awhite solid (mp 57-59° C.) (59%): TLC R_(f) 0.16 (EtOAc/Hexanes(10:90)); [α]²³D=−21° (c 2.188, CHCl₃); IR (NaCl) 2963, 2868, 2263,1753, 1600, 1563, 1463, 1316, 1153 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.60(d, 2H, J=7.8 Hz), 7.28-7.20 (m, 2H), 7.07 (s, 4H), 5.13 (t, 2H, J=6.3Hz), 4.53 (dd, 2G, J=7.2, 4.8, Hz), 4.16-3.82 (m, 8H), 2.84 (sept, 2H,J=6.9 Hz), 2.50-2.00 (m, 8H), 1.19 (d, 12H, J=6.9 Hz), 1.18 (d, 12H,J=6.3 Hz), 1.12 (d, 12H, J=6.9 Hz), 1.01 (t, 6H, J=7.1 Hz); ¹³C NMR (75MHz, CDCl₃) δ171.8, 153.3, 151.8, 151.7, 141.3, 130.4, 127.8, 126.8,126.1, 123.5, 63.8, 61.0, 60.7, 35.4, 33.9, 29.9, 29.2, 24.8, 24.5,23.3, 13.7; Anal. Calcd for C₅₀H₇₂N₂O₈S₂: C, 67.23; H, 8.12; N, 3.13.Found: C, 66.99; H, 8.19; N, 3.08.

Example 5

Preparation of Bridged di(S-2,4,6-triiso-propylphenylsulfonylproline) 5

diTiPBSP-COOEt 4 (2.1 g, 2.33 mmol) was dissolved in THF (12 ml), and,then, H₂O (6 ml), LiOH.H₂O (323 mg, 7.69 mmol, 3.3 equiv), and ethanol(6 ml) were added. The reaction was stirred at room temperature for five(5) hours, and, then, it was acidified with 0.5 N HCl to a pH of 2. Theacidified mixture was extracted with dichloromethane and separated. Theorganic layer was dried with Na₂SO₄, and the solvent was removed to givea solid. The solid was purified by recyrstalization withchloroform/hexanes to give 2.07 g of bridgeddi(S-2,4,6-triiso-propylphenylsulfonylproline) (“diTiPBSP-COOH”) 5 as awhite solid (mp 86-88° C.) (Quantitative): [α]²⁵D=116° (c 1.256, CHCl₃);IR (NaCl) 3062, 2961, 2929, 2876, 2759, 2648, 2569, 2261, 1726, 1604,1561, 1460, 1434, 1365, 1317, 1248, 1158 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)δ11.07 (s, 2H), 7.70 (s, 1H), 7.20-6.95 (m, 5H), 6.81 (s, 2H), 4.93 (t,2H, J=6.3 Hz), 4.73 (t, 2H, J=6.5 Hz), 3.98 (sept, 4H, J=6.6 Hz), 2.82(sept, 2H, 6.6 Hz), 2.60-2.00 (m, 8H), 1.18 (d, 12H, J=6.6 Hz), 1.12 (d,12H, J=6.3 Hz), 0.99 (d, 12H, J=6.6 Hz); ¹³C NMR (75 MHz, CDCl₃) 5178.3, 153.6, 151.7, 141.1, 129.9, 127.6, 126.7, 126.4, 123.5, 64.2,60.1, 34.1, 33.9, 30.4, 29.2, 29.1, 24.7, 24.6, 23.3; Anal Calcd. forC₄₆H₆₄N₂O₈S₂: C, 66.00; H, 7.71; N, 3.35. Found: C, 65.71; H, 7.93; N,3.22.

Example 6

Preparation of Dirhodium Bis [bridged-di(S-2,4,6-triisopropylphenylsulfonylprolinate)] 6

diTiPBSP-COOH 5 (1.00 g, 1.2 mmol) and rhodium acetate (240 mg, 0.54mmol) were dissolved in chlorobenzene (35 ml). The solution was refluxedthrough a soxhlet extractor containing calcium carbonate for 72 hours.The solution was then cooled, and the solvent was removed under reducedpressure. The residue was purified by chromatography on silica usingEtOAc/hexanes (1:9) to give 484 mg of dirhodiumbis[bridged-di(S-2,4,6-triisopropylphenyl-sulfonylprolinate)] as a greensolid (48%): TLC R_(f) 0.18 (EtOAc/hexanes (10:90)); IR (NaCl) 2966,2929, 2871, 1603, 1417, 1321, 1161 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.10(s, 8H), 6.97 (t, 2H, J=7.4 Hz), 6.81 (d, 4H, J=8.4 Hz), 6.80 (s, 2H),4.63 (t, 4H, J=8.2 Hz), 4.39 (d, 4H J=7.6 Hz), 3.47 (sept, 8H, J=6.4Hz), 2.96 (sept, 4H, J=6.8 Hz), 2.41 (dd, 4H, 12.2, 6.0 Hz), 2.24-2.14(m, 4H), 2.14-2.00 (m, 4H), 1.76-1.63 (m, 4H), 1.31 (d, 12H, J=6.8 Hz),1.29 (d, 12H, J=6.8 Hz), 1.05 (d, 24H, J=6.8 Hz), 0.94 (d, 24H, J=6.0Hz); ¹³C NMR (75 MHz, CDCl₃) δ190.5, 153.1, 151.4, 141.6, 130.5, 127.1,127.0, 124.7, 123.6, 64.7, 62.3, 34.9, 34.0, 29.3, 27.8, 25.0, 24.6,23.5; HRMS (FAB) calcd for C₉₂H₁₂₅N₄O₁₆S₄Rh₂ 1875.6084, found 1875.6076.

Example 7

Regio-, Diastereo-, and Enantio-selective C—H Insertions ofAryldiazoacetates Into Cyclic N-BOC Protected Amines

This example demonstrates that highly regio-diastereo- andenantioselective C—H insertions of aryldiazoacetates into cyclic N-BOCprotected amines can be achieved by using dirhodiumtetrakis(S-4-dodecylphenylsulfonylprolinate) (“Rh₂(S-DOSP)₄”), which hasthe following formula:

and by using dirhodiumbis[bridged-di(S-4-t-butylphenylsulfonylprolinate)](“Rh₂[bridged(S-TBSP)₂]₂”), which has the following formula:

in which each R represents a 4-t-butylphenyl group. Rh₂(S-DOSP)₄ waspurchased commercially from Aldich, and Rh₂[bridged(S-TBSP)₂]₂ was madeusing the procedures set forth in Examples 1-6, above, except thatdiamine 3 was reacted with 4-t-butylbenzenesulfonyl chloride instead of2,4,6-triisopropylbenzenesulfonyl chloride.

The highly regio-, diastereo-, and enantioselective C—H insertion ofaryldiazoacetates into cyclic N-BOC protected amines was carried outusing Rh₂(S-DOSP)₄ in the following reaction Scheme II:

Briefly, methyl phenyldiazoacetate (9, Ar=phenyl) was prepared frommethyl diazoacetate by the general method set forth in Davies et al.,“Direct Synthesis of Furans From Rhodium(III) Stabilized Carbenoids WithAlkenes,” Org. Synth., 70:92-99 (1991), which is hereby incorporated byreference. To 5 ml of hexanes were added of N-BOC pyrrolidine (10)(0.351 g, 2 mmol, 2 equiv) and Rh₂(S-DOSP)₄ (0.019 g, 0.01 mmol, 0.01equiv). The mixture was chilled to −50° C., and methylphenyldiazoacetate (0.176 g, 1 mmol, 1 equiv) in 10 ml hexanes wasadded. The mixture was stirred for 12 hours and then warmed slowly toroom temperature. The solvent and excess N-tert-butyl-pyrrolidinecarboxylate were removed on a rotary evaporator and by kugelrohrdistillation. The crude product was treated with TFA (10 equiv) at roomtemperature for one hour and was thrice extracted with water. Theaqueous phase was basified to pH 10-11 with NaHCO₃ and thrice extractedwith methylene chloride. The combined organic layers were dried withMgSO₄ and concentrated to give the free amine (11 (Ar=phenyl)) in 96:4dr (by ¹H-NMR). To calculate yield, the free amine (11 (Ar=phenyl)) wasconverted to its hydrochloride salt by dissolving the free amine inethyl ether (5 ml), adding an excess of a 1 M HCl/diethyl ethersolution, filtering the resulting precipitate, washing the collectedsolid with diethyl ether, and drying the resulting white solid. Theoverall yield was 183 mg or 72%.

In like manner, the above reaction was repeated for other methylaryldiazoacetates, and the results are presented in Table I, below:

TABLE I Ar yield, % ee, % de, % a Ph 72 94 92 b p-Cl-Ph 70 94 94 cp-Me-Ph 67 93 94 d 2-Naphthyl 49 93 92

In Table I, the diastereoselectivity of the formation of 11 wasdetermined from the ¹H NMR of the crude amine after extraction andremoval of solvent. The yields for 11a and 11c-11e represent the amountsof crystalline hydrochloride salt that was obtained after treating thecrude amine with ethereal HCl. The yield of 11b represents the pureamine after purification by column chromatography. Theenantioselectivity was determined by conversion of the crude amine toits trifluoroacetamide derivative followed by chiral HPLC or GCanalysis. The relative stereochemistry of 11c was readily determined byconverting 11c to a fused β-lactam in which the cis arrangement of the 2protons in the β-lactam ring was assigned on the basis of a distinctivecoupling (J=5.1 Hz) and nOe experiments (Coulton et al., Chem Soc.Perkin Trans. I, 1998:1193-1202, which is hereby incorporated byreference). The absolute stereochemistry of 11a was determined to be(2S, 2′R) using the Mosher amide method described in Hoye et al., Org.Chem., 61:8489-8495 (1996), which is hereby incorporated by reference.

The next issue that was examined was whether a second C—H insertion wasa feasible process. The reactions and results are summarized in SchemeIII, below:

The reactions were carried out on enantiomerically pure 12 which wasobtained from 11a that was first recrystallized as its hydrochloridesalt to obtain enantiomerically pure material and then treated with(BOC)₂O. Reaction of 12 with the phenyldiazoacetate 9a (4 equiv) usingRh₂(S-DOSP)₄ as catalyst in 2,3-dimethylbutane as solvent resulted inthe formation of 13a in 93% yield. The compound was shown to beC₂-symmetric because, in the ¹³C NMR, only 9 signals were apparent.Since the compound is chiral, this rules out the meso diastereomer. Incontrast, reaction of 12 with excess 9a using Rh₂(R-DOSP)₄ (sometimesdenoted “14” hereinafter) as the catalyst, resulted in the formation ofmixture of diastereomers and/or regioisomers that were not resolvable.

Further experimentation demonstrated that the C₂-symmetric amines couldbe formed in a single step, as shown in Scheme IV, below:

Briefly, Rh₂(S-DOSP)₄-catalyzed decomposition of 9a (1.5 equiv) at −50°C. in the presence of N-BOC-pyrrolidine 10 followed by warming thereaction to 58° C. and addition of a further 4.5 equiv of 9a generatedthe C₂-symmetric amine 13a in 78% yield and 97% ee. Similar bis C—Hinsertion reactions were carried out with aryldiazoacetates 9b-9e toproduce the amines 13b-13e, as summarized in Table II, below:

TABLE II Ar yield, % ee, % a Ph 78 97 b p-Cl-Ph 50 96 c p-Me-Ph 51 96 d2-Naphthyl 62 88 e p-MeO-Ph 40 97

These amines are appropriately functionalized for further conversion byester reduction or Grignard addition to highly functionalized andpotentially useful C₂-symmetric bases.

Experiments were performed to determine whether it would be feasible tocarry out a similar reaction using N-BOC-piperidine, which would providea direct synthesis of threo-methylphenidate (RITALIN™). The experimentsand results are summarized in Scheme V and Table III, below:

TABLE III Rh equiv 16 + 17 16:17 catalyst of 15 yield, % ratio 16 ee, %17 ee, % 7 4.0 49 43:57 34 (2S) 81 (2S) 7 0.25 86 50:50 25 (2S) 79 (2S)8 0.25 73 71:29 86 (2R) 65 (2R)

As shown above in Scheme V and Table III, Rh₂(S-DOSP)₄ 7 catalyzeddecomposition of methyl phenyldiazoacetate 9a in the presence ofN-BOC-piperidine (15, 4 equiv) in 2,3-dimethylbutane at room temperaturefollowed by treatment with trifluoroacetic acid resulted in theformation of a mixture of threo and erythro methyphenidate, 16 and 17,in 49% yield. However, the threo isomer 16 was the minor diastereomerand was formed in only 34% ee. The combined yield of 16 and 17 wasimproved to 86% by using the N-BOC-peperidine as the limiting reactant.This result is different to what was observed with N-BOC-pyrrolidine,which gave bis C—H insertion when an excess of phenyldiazoacetate wasused. A major improvement in enantioselectivity and diastereoselectivitywas achieved by carrying out the reaction with theRh₂[bridged(S-TBSP)₂]₂ 8 catalyst. The ratio of 16:17 (73% yield) wasimproved to 2.5:1 and (2R, 2′R)-threo isomer 16 was formed in 86% ee and52% isolated yield. As shown in Table III, Rh₂[bridged(S-TBSP)₂]₂ 8results in opposite asymmetric induction to Rh₂(S-DOSP)₄ 7, and, in thereaction of 9a and 15 catalyzed by 8, the biologically active enantiomerof threo-methylphenidate is formed.

The erythro diastereomer of methylphenidate 17 was produced by carryingout the reaction with dihydropyridine 18 as illustrated in Scheme Va,below:

Refering to Scheme Va, Rh₂(S-DOSP)₄ catalyzed decomposition of 9a in thepresence of 18 (4 equiv) in 2,3-dimethylbutane at room temperaturefollowed by treatment with TFA resulted in a 63% yield of C—H insertionproducts 19 and 20. The erythro diastereomer 20 was the majordiastereomer (62% de) and was isolated in 53% yield and 80% ee.Determination of the relative and absolute stereochemistry of 20 as (2S,2′R) was readily achieved by converting 20 to erythro-methylphenidate 17by catalytic hydrogenation using hydrogen and a paladium hydrogenationcatalyst.

Example 8

Intermolecular C—H Insertion Reactions Between Allyl Silyl Ethers andMethyl Aryldiazoacetates

This example describes further studies to explore the scope of theasymmetric intermolecular C—H insertion with particular emphasis on thechemoselectivity and diastereoselectivity of the reaction.

Simple allyloxy substrates and Rh₂[(±)-DOSP]₄ (sometimes denoted “21”hereinafter) as catalyst were initially used to study the selectivity ofthe C—H insertions. These reactions are summarized in Scheme VI, below:

In the case of the reaction of 4-chlorophenyldiazoacetate 22 with allylacetate 23 (2 equiv) at room temperature, cyclopropanation was theexclusive reaction, and 24 was formed in 75% yield. In contrast, in thereaction of 22 with allyl silyl ether, the C—H insertion product 27 wasthe major product, and, remarkably, it was formed in >94% de.Interestingly, it appears that the Rh₂[(±)-DOSP]₄ catalyst has a majorinfluence on the product distribution because, when the reaction iscarried out with dirhodium tetraoctanoate, Rh₂(OOct)₄, as catalyst, theratio of cyclopropane 26 to C—H insertion product 27 was 2.5:1. Noreaction occurred with the dirhodium tetracarboxaminde catalyst,Rh₂(R-MEPY)₄ (see Davies, which is hereby incorporated by reference),under these reaction conditions.

The preferential formation of the C—H insertion product 27 is anunprecedented result, because mono-substituted alkenes generally undergocyclopropanation in high yield on reaction with methylphenyldiazoacetate. On repeating the reaction with more highlysubstituted allyl ethers 28, cyclopropanation could be fully eliminated.This is illustrated in Scheme VII and Table IV below:

TABLE IV R¹ R² yield, % de, % a H Me 48 66 b Me Me 44 70 c Me H 72 >94

However, the diastereoselectivity of the C—H insertion was dependent onthe allyl ether substitution pattern. With the trans-dissubstituted ortrisubstituted allyl ethers 28a and 28b, the C—H insertion products 29aand 29b were formed with a syn/anti ratio of about 7:1. However, withthe trans disubstituted allyl ether 28c, the C—H insertion product 29cwas formed in 72% yield and >94% de.

The steric influences on the C—H insertion versus cyclopropanation canbe seen in the reaction with 2-methylpropenyl silyl ether in SchemeVIII, below:

Here, reaction with the 2-methylpropenyl silyl ether 30 results in theformation of the cycloproane 31 without any evidence showing formationof the C—H insertion product. It is believed that, because thearyldiazoacetate cyclopropanation is nonsynchronous, the silyl ether 30has an accessible vinyl terminus for cyclopropanation, while the methylsubstituent in 30 is presumably interfering with the C—H insertion.

Having thus discovered that the trans allyl silyl ether is a promisingsubstrate for diastereoselective C—H insertion, the study was extendedto explore the issue of asymmetric induction within this system.Rh₂(S-DOSP)₄ 7 catalyzed decomposition of 22 in the presence of a seriesof allyl silyl ethers was carried out using the following procedure. Aflame dried 50 ml round bottom flask equipped with a magnetic stir barand a rubber septum was charged with silyl ether (1.5 mmol),Rh₂(S-DOSP)₄ (14 mg, 7.5×10⁻³ mmol), and dry hexane (0.5 ml), and themixture was stirred under argon at room temperature to give a greensolution. A 10 ml gastight syringe was charged withp-chlorophenyldiazoacetate (0.75 mmol) in dry hexane (7.5 ml) to give a0.10 M diazo solution. Addition via syringe pump was initiated at a rateof 7.5 ml/h (1 h addition time), and the green color of the reactionmixture was maintained during the entire addition. After the diazoaddition was complete, the reaction mixture was allowed to stir for anadditional hour, and then the solvent and excess silyl ether wereremoved under reduced pressure. The residue was purified by flashchromatography on silica gel using 96:4 petroleum ether:ether to givethe product as a clear oil. The reaction is set forth in Scheme IX, andthe results are summarized in Table V below:

TABLE IV Product R yield, % de, % de, % 33a Me 72 >94 80 33b Ph 55 >9485 33c CH═CH₂ 41 >94 74 33d H 35 >94 90

In all instances, the diastereocontrol was >94% de favoring the synisomer, and the enantioselectivity ranged from 74-90% ee.

In order to determine the absolute 10 stereochemistry of the C—Hinsertion product, the Rh₂(S-DOSP)₄ catalyzed reaction of methylphenyldiazoacetate 34 with allyl silyl ether 35 was examined. Thereaction is set forth in Scheme X, below:

The reaction resulted in the formation of syn isomer 36 as the majorproduct in 52% yield (2.8:1 ratio of 36 to cyclopropane product) and 92%ee. Lithium aluminum hydride reduction of 36, followed by conversion ofthe alcohol to its t-butoxymethoxy derivative and silyl deprotectiongave 37. The optical rotation of 37 was compared with the value given inGuanti et al., Tetrahedron, 51:10343-10360 (1995), which is herebyincorporated by reference. The absolute stereochemistries of other C—Hinsertion products are tentatively assigned assuming a similar mode ofasymmetric induction for all the substrates.

In summary, these studies, demonstrate that the intermolecular C—Hinsertions of carbenoids derived from aryl diazoacetates is a practicalmethod for the asymmetric synthesis of products that are typicallyderived from an aldol reaction. The reaction proceeds with good chemo-and diastereoselectivity, and by using Rh₂(R-DOSP)₄ as catalyst,reasonably high levels of asymmetric induction can be obtained. Oneparticularly attractive feature of this chemistry is the low molarequivalent of catalyst that is required.

Example 9

Catalytic Asymmetric Synthesis of Diarylacetates and4,4-dirarylbutanoates

This example illustrates a method for the synthesizing diarylacetatesand 4,4-diarylbutanoates using asymmetric carbenoid transformations. Thepractical utility of this methodology is demonstrated by a short formalsynthesis of the antidepressant (−)-sertraline, which has the formula:

Briefly, the method involves reacting methyl phenyldiazoacetate 39 with1,3-cyclohexadiene 40 in the presence of Rh₂(S-DOSP)₄ 7, and thereaction preferentially formed the C—H insertion product 41 rather thanthe cyclopropanated product 42. The C—H insertion product 42 was formedas an inseparable 4:1 mixture of diastereomers, and, so, in order todetermine the extent of the asymmetric induction, 42 was reduced to theknown cyclohexane 43, which was formed in 92% ee (R-configuration). Aneven more effective C—H insertion was achieved on reaction of 39 with1,4-cyclohexadiene 44, as this resulted in the formation of the C—Hinsertion product 45 with very little occurrence of the cyclopropanationreaction. The absolute stereochemisty of 45 was determined to be R byreduction of 45 to the cyclohexane 43 (80% overall yield from 39 with a91% ee). These reactions are summarized in Scheme XI, below:

The reaction with 1,4-cyclohexadiene could be carried out with a rangeof aryldiazoacetates 46 as illustrated in Scheme XII and Table VI,below:

TABLE VI Ar yield 47, % ee 47, % yield 48, % ee 48, % a p-Cl-Ph 84 95 8695 b p-Me-Ph 84 94 89 94 c p-MeO-Ph 69 93 87 93 d 2-naphthyl 64 92 88 92

In each case, the C—H insertion product 47 was produced in >90% ee.Furthermore, 47 could be readily oxidized by DDQ to the diarylacetate 48without racemization. The absolute stereochemistry for 47 and 48 istentatively assigned on the assumption the asymmetric induction wouldparallel that observed in the formation of 45.

The new strategy to 4,4-diarylbutanoates was discovered on attemptingthe C—H insertion reaction with the phenylvinyldiazoacetate 49. Reactionof 49 with 1,3-cyclohexadiene 40 did not result in the formation of theexpected C—H insertion product. Instead, the 1,4-cyclohexadiene 50 wasformed in 63% yield and 98% ee. A side product in this reaction is thecyclopropanation/Cope rearrangement product 51, as shown in Scheme XIII,below:

The catalyst has a major effect on the product distribution in thisreaction, as shown in Table VII, below:

TABLE VII Rh catalyst 50:51 Rh₂(S-DOSP)₄ 86:14 Rh₂(OOct)₄ 26:74Rh₂(OPiv)₄ 19:81 Rh₂(TFA)₄ 46:54 Rh₂(TPA)₄ 30:70

In Table VII, Rh₂(OOct)₄ represents dirhodium(II) tetraoctanoate,Rh₂(OPiv)₄ represents dirhodium(II) tetra(trimethylacetate), Rh₂(TFA) ₄represents dirhodium(II) tetra(trifluoroacetate), and Rh₂(TPA)₄represents dirhodium(II) tetra(triphenylacetate). For example, whenRh₂(OOct)₄ is used as catalyst, cyclopropanation becomes the preferredreaction. From the range of catalysts that were studied, it appears thatcatalyst exhibits a subtle combination of steric and electronic effects.At present, Rh₂(S-DOSP)₄ is the best catalyst for limiting thecyclopropanation reaction, resulting in a 84:16 ratio of 50:51.

One possible mechanism for the formation of cyclohexadiene 50 would bean allylic C—H insertion between 49 and 1,3-cyclohexadiene 40 to form 52which could then undergo a Cope rearrangement to form 50, as shown inScheme XIV, below:

However, there is no apparent driving force for the Cope rearrangementof 50 and 52. Indeed, there is evidence that the driving force for theCope rearrangement is in the reverse direction by heating 50 inrefluxing hexane, because, under these conditions, 50 slowly rearrangesto 52. In view of this, alternative mechanistic possibilities need to beconsidered. It is conceivable that 50 is derived by an intercepted C—Hinsertion process or by means of an ene reaction where thevinylcarbenoid reacts as a 2n system.

The reaction described in Scheme XIII was extended to a range ofarylvinyldiazoacetates, as illustrated in Scheme XV and Table IX, below:

TABLE IX Ar yield 54, % ee 54, % a p-MeO-Ph 58 99 b 3,4-diClPh 59 99 c2-naphthyl 50 99 d o-MeO-Ph 17 86 e 1-naphthyl 22 84

Each of the reactions was performed using the following generalprocedure, which is illustrated using methyl3,4-dichlorophenylvinyldiazoacetate 53b as a reactant. A solution of thevinyldiazoacetate 53b (207 mg, 0.764 mmol) in dry hexanes (20 ml) wasadded dropwise over 15 minutes to a flame-dried flask containing astirred solution of Rh₂(S-DOSP)₄ (12 mg, 6.4×10⁻³ mmol) and the diene(0.4 ml, 4 mmol) in dry hexane (30 ml) at room temperature. After 16hours, the solvent was removed under reduced pressure. Purification byflash silica gel column chromatography (petroleum ether/ether, 9:1,R_(f)=0.24) gave 54b in 59% yield as a clear oil. 99% ee (determined byHPLC: Daicel-OD, 0.8% i-Pr-OH in hexanes, 0.8 ml/min; Tr=12.06 min(minor), 23.73 min (major)). [α]²⁵ _(D)=+4° (c 2.0 8, CHCl₃). IR (neat)3029, 2954, 2863, 2817, 1726, 1651 cm⁻¹; ¹H NMR (300 MHz) δ7.36 (d, 1 H,J=8.0 Hz), 7.27 (d, 1H, J=2.5 Hz), 7.10 (dd, 1H, J=15.5 Hz), 7.02 (dd,1H , J=8.0, 2.5 Hz), 5.81 (d, 1H, 15.5 Hz), 5.75 (Br. d, 2H, J=12.0 Hz),5.57 (Br. d, 1H, J=10.0 Hz), 5,43 (Br. d, 1H, J=10.0 Hz), 3.71 (s, 3H) ,3.38 (dd, 1H, J=8.5, 8.0 Hz), 3.17-3.15 (m, 1H) 2.62-2.48 (m, 2H); ¹³CNMR (125 MHz) δ166.5, 148.1, 140.7, 132.4, 130.8, 130.4, 130.2, 127.6,126.83, 126.79, 125.7, 125.3, 122.9, 53.6, 51.6, 40,1, 26.3. HRMS calcdfor C₁₇H₁₆O₂Cl₂, 322.0527, found, 322.0504.

The reactions with m- or p-substituted benzene (53a, 53b) or 2-naphthylderivatives (53c) result in the formation of 54a-54c with exceptionallyhigh levels of asymmetric induction (99% ee). In contrast, the reactionwith o-substituted benzene (53d) and 1-naphthyl (53e) result in theformation of 54d and 54e with lower enantioselectivity (84-86% ee).Also, the yields of 54d and 54e were greatly decreased compared to54a-54c, because, it is believed, the major product in these last tworeactions was the cyclopropanation/Cope rearrangement product, analogousto 51.

The cyclohexadiene 54b is an excellent precursor for the formalsynthesis of (−)-sertraline, as illustrated in Scheme XVI, below:

Oxidation of 54b with DDQ followed by catalytic hydrogenation over Pd/Cformed the 4,4-diarylbutanoate 55 (52% yield for 3 steps from 53b) withminimal racemization (96% ee). Ester hydrolysis of the4,4-diarylbutanoate 55 followed by an intramolecular Freidel-Craftsacylation generated the tetralone 56 in 79% yield for 2 steps.Conversion of the tetralone 56 to (−)-sertraline 57 was carried outfollowing the method described in Corey, which is hereby incorporated byreference.

The general chemistry described in this example is applicable to othervinylcarbenoid systems as illustrated in Scheme XVII, below:

Rh₂(S-DOSP)₄-catalyzed decomposition of the cyclic vinyldiazoacetate 58in the presence of 1,3-cyclohexadiene 40 resulted in the formation ofthe 1,4-cyclohexadiene 59 in 73% yield and 97% ee. The absoluteconfiguration of compound 59 was determined by DDQ oxidation andozonolysis to afford the 2-phenylcyclohexanone in a 56% yield. Found[α]²⁶ _(D)=−17 (c=1.66, PhH) . Lit. value: [α]²⁴ _(D)=−113.5 (c=0.60,PhH), S-isomer. (Berti et al., J. Chem. Soc., pp. 3371-3377 (1971),which is hereby incorporated by reference.) Similarly, decomposition ofthe dienyldiazoacetate 60 in the presence of 1,3-cyclohexadiene 40resulted in the formation of 61 (60% yield and 99% ee), in which bothdiene components have moved out of conjugation.

Although the invention has been described in detail for the purpose ofillustration, it is understood that such detail is solely for thatpurpose, and variations can be made therein by those skilled in the artwithout departing from the spirit and scope of the invention which isdefined by the claims which are set forth below.

What is claimed is:
 1. A compound having the formula:

wherein M¹ and M² are the same or different and are transition metalatoms or ions; Z² and Z³, independently, are the atoms necessary tocomplete a 3-12 membered heterocyclic ring; Z¹ is an alkylene or arylenegroup; Q¹ and Q² are the same or different and are electron withdrawinggroups; L¹ and L³, taken together, represent —O—CR¹³—O—; L² and L⁴,taken together, represent —O—CR¹⁴—C—; and R¹³ and R¹⁴ are the same ordifferent and are selected from the group consisting of alkyl groups andaryl groups or R¹³ and R¹⁴ represent alkylene or arylene groups that aredirectly or indirectly bonded to one another.
 2. A compound according toclaim 1, having the formula:


3. A compound according to claim 1, wherein M¹ and M²are independentlyselected from Rh, Ru, Mo, Pd, and Re.
 4. A compound according to claim1, wherein each of M¹ and M² is Rh.
 5. A compound according to claim 1,wherein Q¹ is selected from the group of moieties having the formulae—C(O)R¹, —SO₂R¹, and —P(O)R¹R^(1′); wherein Q² is selected from thegroup of moieties having the formulae —C(O)R², —SO₂R², and—P(O)R²R^(2′); and wherein each of R¹, R^(1′), R², and R^(2′) isindependently selected from an alkyl group, an aryl group, and an alkoxygroup.
 6. A compound according to claim 5, wherein Q¹ has the formula—SO₂R¹; Q² has the formula —SO₂R²; and R¹ and R² are the same ordifferent and are alkyl or aryl groups.
 7. A compound according to claim6, wherein each of R¹ and R² is independently selected from the groupconsisting of 4-(t-butyl)phenyl, 2,4,6-trimethylphenyl, and2,4,6-triisopropylphenyl.
 8. A compound according to claim 1, wherein Z²and Z³ each have the formula —CH₂CH₂—.
 9. A compound according to claim1, wherein Z¹ is 1,3-phenylene.
 10. A compound according to claim 1having one of the following formulae:


11. A compound according to claim 1 having one of the followingformulae:


12. A compound according to claim 1 having one of the followingformulae:

wherein R¹ and R² are the same or different and are alkyl or arylgroups.
 13. A compound comprising: a first metal atom and a second metalatom bonded to one another along an axis and two carboxylate ligandswherein each of said two carboxylate ligands comprises two carboxylategroups bonded to each other via a moiety having the formula:

wherein Z¹⁰ and Z¹¹, together with the atoms to which they are bondedform a 3-12 membered ring; wherein Z^(10′) and Z^(11′), together withthe atoms to which they are bonded form a 3-12 membered ring; whereinR⁷⁸, R^(78′), R⁷⁹, and R^(79′) are independently selected from the groupconsisting of H, an alkyl group, and an aryl group; wherein Z¹² is analkylene or arylene group; wherein each of said two carboxylate groupscomprises a first carboxylate oxygen atom (“O¹”), a second carboxylateoxygen atom (“O²”), and a carbon (“C”) to which said O¹ and said O² arebonded thereby forming two O¹—C—O² moieties, each O¹—C—O² moietydefining a plane which is substantially parallel to said axis; whereinsaid O¹ of each of said two carboxylate groups of each of said twocarboxylate ligands is bonded to said first metal atom; wherein said O²of each of said two carboxylate groups of each of said two carboxylateligands is bonded to said second metal atom; wherein each of said twocarboxylate ligands further comprises at least two chiral centers; andwherein said compound has D₂ symmetry.
 14. A compound according to claim13, wherein none of Z¹⁰, Z^(10′), Z¹¹, and Z^(11′) represents a directbond between the carbon atoms to which they are bonded.
 15. A compoundaccording to claim 14, wherein at least one of Z¹⁰ and Z^(10′) has theformula —NQ—, at least one of Z¹¹ and Z^(11′) is an arylene or alkylenegroup, and Q is an electron withdrawing group.
 16. A method for making acompound having the formula:

wherein M¹ and M² are the same or different and are transition metalatoms or ions; Z² and Z³, independently, are the atoms necessary tocomplete a 3-12 membered heterocyclic ring; Z¹ is an alkylene or arylenegroup; and Q¹ and Q² are the same or different and are electronwithdrawing groups; L¹ and L³, taken together, represent —O—CHR¹³—O—; L²and L⁴, taken together, represent —O—CHR¹⁴—O—; and R¹³ and R¹⁴ are thesame or different and are selected from the group consisting of alkylgroups and aryl groups or R¹³ and R¹⁴ represent alkylene or arylenegroups that are directly or indirectly bonded to one another, saidmethod comprising: providing a ligand having the formula:

or a mixture thereof, wherein each of A¹ and A² is independentlyselected from the group consisting of a hydrogen atom and an electronwithdrawing group and each of R³ and R⁴ is independently selected fromthe group consisting of H, alkyl, and aryl; and converting the ligandwith a bis-metal salt under conditions effective to produce thecompound.
 17. A method according to claim 16, wherein Z² and Z³ eachhave the formula —CH₂CH₂—; each of M¹ and M² is Rh; Z¹ is 1,3-phenylene;Q¹ is selected from the group of moieties having the formulae —C(O)R¹,—SO₂R¹, and —P(O)R¹R^(1′); Q² is selected from the group of moietieshaving the formulae —C(O)R², —SO₂R², and —P(O)R²R^(2′); and each of R¹,R^(1′), R², and R^(2′) is an alkyl group, an aryl group, or an alkoxygroup.
 18. A method according to claim 16, wherein the bis-metal salthas the formula M¹M²(OOR⁵)₄, wherein R⁵ is an alkyl group or an arylgroup.
 19. A method according to claim 16, wherein each of M¹ and M² isRh and the bis-metal salt is Rh₂(OOCH₃)₄.
 20. A compound having one ofthe following formulae:

wherein Z² and Z³, independently, are the atoms necessary to complete a3-12 membered heterocyclic ring; Z¹ is an alkylene or arylene group; A¹and A² are independently selected from the group consisting of ahydrogen atom and an electron withdrawing group; and each each of R³ andR⁴ is independently selected from the group consisting of H, alkyl, andaryl.
 21. A method for preparing an N-substituted compound having theformula:

wherein Z² and Z³, independently, are the atoms necessary to complete a3-12 membered heterocyclic ring; Z¹ is an alkylene or arylene group; A³and A⁴ are the same or different and are electron withdrawing groupshaving the formulae —C(O)R², —SO₂R², or —P(O)R²R^(2′); each of R¹,R^(1′), R², and R^(2′) is an alkyl group, an aryl group, or an alkoxygroup; and each of R³ and R⁴ is independently selected from the groupconsisting of H, alkyl, and aryl, said method comprising: providing anN-unsubstituted compound having the formula:

wherein R⁶ and R⁷ is independently selected from an alkyl group or anaryl group; and converting the N-unsubstituted compound to theN-substituted compound with an acylating agent, a sulfonylating agent,or a phosphonylating agent.
 22. A method for preparing anN-unsubstituted compound having the formula:

wherein Z² and Z³, independently, are the atoms necessary to complete a3-12 membered heterocyclic ring; Z¹ is an alkylene or arylene group; andR⁶ and R⁷ is independently selected from an alkyl group or an arylgroup, said method comprising: providing an unsaturated heterocycliccompound having the formula:

and converting the unsaturated heterocyclic compound to theN-unsubstituted compound using hydrogenation.
 23. A compound having oneof the following formulae:

wherein Z² and Z³, independently, are the atoms necessary to complete a3-12 membered heterocyclic ring; Z¹ is an alkylene or arylene group; andR⁶ and R⁷ is independently selected from an alkyl group or an arylgroup.
 24. A compound according to claim 23, wherein Z¹ is a1,3-phenylene group.
 25. A method for preparing an unsaturatedheterocyclic compound having the formula:

wherein Z² represents the atoms necessary to complete a 3-12 memberedheterocyclic ring; Z¹ is an alkylene or arylene group; and R⁶ isselected from an alkyl group or an aryl group, said method comprising:providing a cyclic ketone having the formula:

wherein R⁸ is an amine-protecting group; and converting the cyclicketone to the N-unsaturated heterocyclic compound with a bis-lithiumcompound having the forrmula Z¹Li₂.
 26. A method according to claim 25,wherein the bis-lithium compound is 1,3-dilithiobenzene.
 27. A methodaccording to claim 25, wherein the N-unsaturated heterocyclic compoundhas the formula:

and the cyclic ketone has the formula:

or wherein the N-unsaturated heterocyclic compound has the formula:

and the cyclic ketone has the formula:


28. A method of producing a compound having the formula:

where R¹, R², and R³ are independently selected from H, alkyl, aryl, orvinyl or where R¹ and R³, together with the atoms to which they arebonded, form a 5-12 membered ring; Y is an electron withdrawing group; Xis NR¹¹; R³¹ and R³², taken together with the atoms to which they arebonded, form a ring having the formula:

R⁴¹, R⁴², and R⁴³ are independently selected from H, alkyl, aryl, orvinyl or R⁴¹ and R⁴³, together with the atoms to which they are bonded,form a 5-12 membered ring; Y′ is an electron withdrawing group; m is2-9; R¹¹ is H, an alkyl group, an aryl group, an acyl group, analkoxycarbonyl group, or a silyl group having the formula —SiR³³R³⁴R³⁵;R³⁰ is selected from the group consisting of H, alkyl, aryl, and vinyl;and R³³, R³⁴, and R³⁵ are independently selected from an alkyl group andan aryl group; said method comprising: providing a diazo compound havingthe formula:

and converting the diazo compound with a cyclic amine having theformula:

in the presence of a bis-transition metal catalyst and under conditionseffective to produce the compound.
 29. A method according to claim 28,wherein the compound has the formula:


30. A method of producing a compound having the formula:

wherein R¹, R², and R³ are independently selected from H, alkyl, aryl,or vinyl or where R¹ and R³, together with the atoms to which they arebonded, form a 5-12 membered ring; Y is an electron withdrawing group; Xis CH₂, O, or NR¹¹; R¹¹ is H, an alkyl group, an aryl group, an acylgroup, an alkoxycarbonyl group, or a silyl group having the formula—SiR³³R³⁴R³⁵; each of R³⁰ and R³¹ is independently selected from thegroup consisting of H, alkyl, aryl, and vinyl; R³² is an alkyl group, anaryl group, an acyl group, an alkoxycarbonyl group, or a silyl grouphaving the formula —SiR³⁶R³⁷R³⁸; and R³³, R³⁴, R³⁵, R³⁶, R³⁷, and R³⁸are independently selected from an alkyl group and an aryl group;provided that when each of R³⁰ and R³¹ is H, X is not CH₂, said methodcomprising: providing a diazo compound having the formula:

and converting the diazo compound with a material having the formula:

 in the presence of a bis-transition metal catalyst and under conditionseffective to produce the compound, wherein X′ is CH₂, O or NR^(11′);R^(11′) is an alkyl group, an aryl group, an acyl group, analkoxycarbonyl group, or a silyl group having the formula —SiR³⁶R³⁷R³⁸;and R³³, R³⁴, and R³⁵ are independently selected from an alkyl group andan aryl group.
 31. A method according to claim 30, wherein X is O, R³²is a trialkylsilyl group or a triarylsilyl group, and R³¹ is H.
 32. Amethod according to claim 30, wherein X is NR¹¹, R¹¹ is am alkyl group,and R³² is selected from an acyl group and an alkoxycarbonyl group. 33.A method according to claim 30, wherein R¹ and R³ are independentlyselected from H, alkyl, aryl, or vinyl.
 34. A method according to claim30, wherein R¹ and R³, together with the atoms to which they are bonded,from a 5-12 membered ring.